Hypothermic Oxygenated (HOPE) Versus Normothermic Machine Perfusion (NMP) in Human Liver Transplantation

NCT ID: NCT04644744

Last Updated: 2022-07-22

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 213 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-14
• Study Completion Date: 2024-12-31

Brief Summary

The common practice of conventional cold storage (CCS) organ preservation has changed little since the initial introduction of the original University of Wisconsin (UW) organ preservation solution in the late 1980s. CCS relies on hypothermia to decelerate metabolism and reduce oxygen demand in order to prolong the time of ischemia without rapid functional graft impairment, therefore merely delaying graft damage. While CCS only prolongs storage time and limits the damage sustained during the period of cold ischemia, ex-vivo machine perfusion (MP) appears to be capable of reversing some of these effects. Currently, two main paradigms prevail in the clinical approach to liver allograft MP: hypothermic oxygenated MP (HOPE) may be seen as a dynamic alternative of the traditional organ preservation based on hypothermia-induced deceleration of metabolism, which aims to combine the positive effects of hypothermia observed in classical cold storage (e.g. technical simplicity, relative safety, decreased metabolism) with the positive effects of dynamic preservation (e.g. controlled sheer stress mediated gene activation, removal of metabolites, transport of oxygen and ATP recharging). Normothermic perfusion (NMP) aims at re-equilibration of cellular metabolism by preserving the organ at physiological temperatures whilst ensuring sufficient oxygen and nutrient supply. In both approaches, the perpetual circulation and moderate shear-stress sustain endothelial functionality. While past and current clinical trials were designed to compare different MP approaches with CCS as the clinical standard, a direct comparison between different end-ischemic MP techniques (HOPE versus NMP) is still lacking. The purpose of this study is to test the effects of end-ischemic NMP versus end-ischemic HOPE technique in a multicentre prospective randomized controlled clinical trial (RCT) on ECD liver grafts in DBD liver-transplantation (HOPE-NMP). Two-hundred-thirteen (n = 213) human whole organ liver grafts will be submitted to either 4-24 hours of NMP (n = 85) or 2-3 hours of HOPE (n = 85) directly before implantation and going to be compared to a control-group of patients (n = 43) transplanted with static cold storage preserved ECD-allografts. Primary (surgical complications as assessed by the comprehensive complication index [CCI]) and secondary (among others laboratory values, graft- and patient survival, hospital costs, hospital stay) endpoints are going to be analysed.)

Detailed Description

Liver transplantation has evolved as the mainstay of treatment for end-stage liver disease. While the demand for organ transplantation has increased over time, Germany's organ donation rate is low compared to other countries. The main indications for listing are 'fibrosis and cirrhosis' (27%) followed by 'alcoholic liver disease' (23%) and 'hepatic malignancies' (17%).

With the advent of emerging waiting list mortality, several strategies for donor pool expansion are being pursued; these include the use of living donors, splitting of cadaveric livers for two recipients, and the use of extended criteria donor (ECD) allografts for OLT. These ECD-allografts, however, exhibit poor tolerance to ischemia-reperfusion (I/R) injury, an important cause of liver damage. As such, I/R-injury is the underlying cause of graft dysfunction in ECD-allografts and negatively affects the process of liver regeneration in surgical conditions including hepatic resections and OLT.

Machine perfusion with oxygenated blood was already implemented in the first series of 11 successful human OLTs in the 1960s. While the logistical simplicity and reliable performance of CCS led to its quick adoption as the standard solid organ preservation technique, the increased utilization of high-risk organs has unveiled the limitations of CCS, furthering the debate on the impact of different MP techniques. Today, perfusion conditions vary broadly, especially in preclinical research. Parameters under discussion include different temperatures, perfusate composition, the application of perfusion flow (continuous or pulsatile), the timing and duration of the perfusion, starting either at the donor site or applied only end-ischemic in the recipient centre. Two main principles have been translated into clinical practice today: hypothermic oxygenated perfusion (HOPE) and normothermic MP (NMP). The latter differs significantly from HOPE because the allograft is perfused with oxygenated red blood cells or oxygen carriers at physiological temperatures with the aim to reduce the ischemic graft injury by minimizing the duration of cold preservation and perfectly mimicking physiological conditions. A recently completed randomized controlled trial (RCT) by Nasralla et al. proved the feasibility of NMP for OLT and demonstrated a significant reduction in peak AST and subsequent early allograft dysfunction (EAD), however without a significant difference in graft and patient survival. Most recently, a development of the NMP technique that allowed a 7-day preservation of human livers with a sustained metabolic function and an intact liver structure was recently reported by Eshmuminov et al. Based on the sustained full hepatic metabolism during NMP, several groups are currently exploring the possibility of normothermic viability testing. The cellular mechanisms of organ protection by NMP do not center around IRI mitigation and reconditioning, but IRI prevention, and are altogether different from cold perfusion techniques. While normothermic machine perfusion is most effective when applied during the entire period of organ preservation, the end-ischemic application of this technique in the recipient hospital is becoming more popular.

There are two main hypotheses on the underlying mechanisms of HOPE induced organ protection; (I.) modulation of cellular metabolism (energy household, mitochondrial respiration), and (II.) stimulation of the sinusoidal endothelial layer. Although, tissue oxygen consumption is markedly decreased at 4-10 Celsius, it is not completely suspended. The shift of mitochondrial metabolism to anaerobic pathways leads to expressed mitochondrial metabolite accumulation during ischemia and subsequently to extreme radical oxygen species (ROS) generation through rapid re-oxidization by the early reperfusion respiratory burst. The delivery of oxygen during cold preservation can effectively upload cellular energy household via various mitochondrial pathways. Pre-implantation resuscitation of organs with machine perfusion and oxygen can increase tissue ATP levels and decrease the post-ischemic production of ROS and danger-associated molecular patterns (DAMPs), this subsequently leads to a mitigated immune response. This organ conditioning effect is attributed to a controlled re-oxygenation inducing moderate ROS release just before reperfusion. These low levels of ROS are not only responsible for the induction of antioxidant enzymes (heme-oxygenase, gluthathione-synthase, superoxide-dismutase), but are also responsible for the stimulation of protein mediators of innate pro-survival mechanisms. A further mechanism behind the protective effects of dynamic preservation approaches is the presence of shear stress and as such active perfusion during the preservation phase may induce specific shear stress-sensitive genes some of which include Kruppel-like factor 2 or endothelial nitric oxide synthase. Currently, three multicenter RCTs have completed their patient recruitment and clinical results are expected for the year 2021. The Zurich group initiated a multicentric RCT to assess the impact of HOPE on any DBD liver graft including retransplantations and marginal livers and is powered to assess major complications (Clavien grade ≥III) (NCT01317342). The Groningen team explores the dual HOPE (d-HOPE) technique in DCD grafts (NCT02584283) and our own group initiated a multicentric RCT on HOPE in ECD-DBD liver transplantation in 2017 (NCT03124641).

Viability assessment during MP can guide the clinical decision whether to accept a liver for transplantation and is therefore an important emerging tool in ECD OLT. The possibility of a reliable viability assessment is advocated as a considerable advantage of normothermic perfusion techniques. By sustaining full metabolism, NMP allows to analyse several makers of liver function and injury, including biliary parameters (e.g. bile flow, bile glucose, bicarbonate and pH), perfusate pH and base excess, portal venous- and hepatic artery flow and perfusate hepatocellular enzymes. Despite the reduced metabolic activity during cold storage and hypothermic liver perfusion, there is increasing evidence that a prediction of future graft performance after transplantation may be possible during HOPE, as well. Analysis of the cold perfusate during HOPE provides a unique opportunity to identity potential biomarkers which are associated with various post-OLT outcomes. A recent study involving 31 human ECD-DBD grafts initially rejected for transplantation, found that cold perfusion not only ameliorates reperfusion injury but also allows for graft viability assessment. Thus, the 2-hour perfusate AST and lactate dehydrogenase (LDH) correlated significantly with the peak AST after implantation. In two grafts with a significant postreperfusion transaminase release, a high portal perfusion pressure was noted.

The Zurich group has recently presented a new mitochondrial marker to assess viability of entire liver grafts during HOPE. Real-time fluorometric analysis of mitochondrial flavin mononucleotide (FMN) in the HOPE perfusate predicted human liver function, complications and graft loss prior to transplantation. The use of this surrogate parameter could facilitate proper clinical decision making whether to accept or decline allografts in the HOPE setting. This marker is currently validated in other solid organs and also in the RCT of Guarerras working group. Importantly, the quantification of FMN is possible in real time, requiring only a spectroscope to reliably predict graft survival within the first 30-45 minutes of HOPE. The clinical value and head-to-head comparison of various allograft viability parameters in the HOPE vs. NMP setting has yet to be explored in the setting of a large multicenter RCT. With the advent of clinical MP and the context of a dire donation situation in the western world, it will be of utmost clinical importance to identify the most effective dynamic preservation technique. While past and current clinical trials in DCD and DBD liver transplantation were designed to compare different MP approaches with CCS as the clinical standard, a direct comparison between different end-ischemic MP techniques (HOPE versus NMP) is still lacking.

Conditions

Hepatocellular Injury; Liver Transplant Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hypothermic oxygenated perfusion (HOPE)

Application of end-ischemic Hypothermic machine perfusion (HOPE) for a minimum of 2 hours (until hepatectomy)

Group Type: EXPERIMENTAL

Hypothermic oxygenated perfusion (HOPE)

Intervention Type: DEVICE

HOPE for 1 hour via the portal vein in a recirculating and pressure controlled system (2-3 mm Hg), 0.1 ml/g liver/min, perfusion volume 3-4 L, Belzer (UW) machine perfusion solution, perfusate temperature 10 °C, perfusate oxygenation pO2 of 60-80 kPa

Normothermic machine perfusion (NMP)

Application of end-ischemic normothermic machine perfusion (NMP) for a minimum of 4 hours (up to 24 hours)

Group Type: EXPERIMENTAL

Normothermic machine perfusion (NMP)

Intervention Type: DEVICE

End-ischemic NMP will be continued throughout the recipient hepatectomy and until the transplanting team is ready to implant the liver. The minimum protocol-stipulated NMP duration is 4 hours, the time needed for ATP repletion in animal studies. Total NMP preservation time will be according to the official recommendations of the manufacturer (4-24 hours) and at the discretion of the local transplant centre. The liver allograft will be disconnected from the OrganOx metra® device immediately prior to transplantation and flushed with three litres of HTK via the hepatic artery and the portal vein.

Conventional cold storage (CCS)

Conventional cold storage

Group Type: ACTIVE_COMPARATOR

Hypothermic oxygenated perfusion (HOPE)

Intervention Type: DEVICE

HOPE for 1 hour via the portal vein in a recirculating and pressure controlled system (2-3 mm Hg), 0.1 ml/g liver/min, perfusion volume 3-4 L, Belzer (UW) machine perfusion solution, perfusate temperature 10 °C, perfusate oxygenation pO2 of 60-80 kPa

Normothermic machine perfusion (NMP)

Intervention Type: DEVICE

End-ischemic NMP will be continued throughout the recipient hepatectomy and until the transplanting team is ready to implant the liver. The minimum protocol-stipulated NMP duration is 4 hours, the time needed for ATP repletion in animal studies. Total NMP preservation time will be according to the official recommendations of the manufacturer (4-24 hours) and at the discretion of the local transplant centre. The liver allograft will be disconnected from the OrganOx metra® device immediately prior to transplantation and flushed with three litres of HTK via the hepatic artery and the portal vein.

Interventions

Hypothermic oxygenated perfusion (HOPE)

HOPE for 1 hour via the portal vein in a recirculating and pressure controlled system (2-3 mm Hg), 0.1 ml/g liver/min, perfusion volume 3-4 L, Belzer (UW) machine perfusion solution, perfusate temperature 10 °C, perfusate oxygenation pO2 of 60-80 kPa

Intervention Type: DEVICE

Normothermic machine perfusion (NMP)

End-ischemic NMP will be continued throughout the recipient hepatectomy and until the transplanting team is ready to implant the liver. The minimum protocol-stipulated NMP duration is 4 hours, the time needed for ATP repletion in animal studies. Total NMP preservation time will be according to the official recommendations of the manufacturer (4-24 hours) and at the discretion of the local transplant centre. The liver allograft will be disconnected from the OrganOx metra® device immediately prior to transplantation and flushed with three litres of HTK via the hepatic artery and the portal vein.

Intervention Type: DEVICE

Other Intervention Names

Hypothermic machine perfusion (HMP)

Eligibility Criteria

Inclusion Criteria

• Signed informed consent
• Patients 18 years or older
• Patients suffering from end stage-liver disease and/or malignant liver tumours
• Listed for OLT
• Receiving ECD-allografts

Exclusion Criteria

• Recipients of split or living donor liver transplants
• Previous liver transplantation
• Combined transplantations (liver-kidney, liver-lung, etc.)
• Participation in other liver related trials
• The subject received an investigational drug within 30 days prior to inclusion
• The subject is unwilling or unable to follow the procedures outlined in the protocol
• The subject is mentally or legally incapacitated
• Patient is not able to understand the procedures due to language barriers
• Family members of the investigators or employees of the participating departments

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Charite University, Berlin, Germany

OTHER

Sponsor Role: lead

Responsible Party

Georg Lurje, MD

Consultant HPB- and Transplant Surgeon

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Georg Lurje, M.D.

Role: PRINCIPAL_INVESTIGATOR

Charite University, Berlin, Germany

Locations

Charité Universitätsmedizin - Berlin, Campus Charité Mitte | Campus Virchow-Klinikum

Berlin, , Germany

Site Status: RECRUITING

University Hospital Bonn, Department of Surgery

Bonn, , Germany

Site Status: RECRUITING

Medizinische Hochschule Hannover (MHH), Department of Surgery and Transplantation

Hanover, , Germany

Site Status: NOT_YET_RECRUITING

University Hospital Heidelberg, Department of Surgery and Transplantation

Heidelberg, , Germany

Site Status: NOT_YET_RECRUITING

Countries

Germany

Central Contacts

Georg Lurje, M.D.

Role: CONTACT

georg.lurje@charite.de

+4930450652339

Facility Contacts

Georg Lurje, M.D.

Role: primary

georg.lurje@charite.de

+4930450652339

Johann Pratschke, M.D.

Role: backup

johann.pratschke@charite.de

Steffen Manekeller, MD

Role: primary

steffen.manekeller@ukbonn.de

Florian Vondran, M.D.

Role: primary

Vondran.Florian@mh-hannover.de

Arianeb Mehrabi, M.D.

Role: primary

arianeb.mehrabi@med.uni-heidelberg.de

Related Links

http://www.hopeliver.com

Study webpage

Other Identifiers

EA2/270/20

Identifier Type: -

Identifier Source: org_study_id