Viability Assessment Using FMN Measured in Perfusate and Bile During Normothermic Machine Perfusion

NCT ID: NCT07315204

Last Updated: 2026-01-07

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 850 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-12-29
• Study Completion Date: 2028-12-31

Brief Summary

Discarded perfusate samples will be collected from donors after circulatory death (DCD) or donors after brain death (DBD) organs during the machine perfusion period prior to transplantation by the study team. FMN will be measured as is standard of care for all machine perfusion liver transplant cases at Cleveland Clinic.

Participating centers will be provided with sample collection and shipping instructions to ensure sample preservation in accordance with IATA guidelines. Samples from outside sites will not be stored for future research and will be discarded once analysis is completed.

After the collection of the samples from machine perfusion, the transplant procedure will continue according to standard process.

Detailed Description

Real-time identification of graft viability is critical to safe expansion of the donor pool. Different strategies for viability testing in Normothermic Machine Perfusion (NMP) have been described by groups from the United Kingdom, The Netherlands, Austria, United States and Switzerland. In general, strategies in NMP utilize clinical observations, perfusion conditions, plus perfusate and bile analyses including lactate clearance, pH, glucose utilization/reuptake and more. At present there is no consensus for viability parameters or certain thresholds, though lactate clearance and clinical observation seem to be the most widely used criteria at present time.

Viability assessment has been reported for Hypothermic oxygenated perfusion (HOPE)-treated grafts, mostly centered around Flavin Mononucleotide (FMN), a marker of mitochondrial injury originating from mitochondrial Complex 1. FMN was shown to be released into perfusate at reoxygenation of previously ischemic tissues and correlating well with posttransplant complications and predicting graft loss beyond certain perfusate thresholds obtained during HOPE. This has led to improvements in graft loss and reduction of clinically relevant non-anastomotic strictures (NAS) with HOPE despite the use of extended criteria DCD livers (any donor age up to 100 years, old donors, >30min functional donor warm ischemia time (fDWIT), up to 8hrs static cold storage before HOPE, macrosteatosis) in Europe. Dr. Schlegel's group has recently validated prior thresholds center wide and internationally repeatedly showing the correlation between perfusate FMN and clinically relevant post-LT outcomes.

The investigators have investigated the utility of perfusate FMN obtained during NMP using the OrganOx metra device predicting graft loss and complications. Specifically, the investigators find that FMN predicts NAS, overall complications and graft loss after transplant. Perhaps most impressively, the investigators find that quantitative measurement of FMN can predict not only binary complications, but also severity of such complications in perfused grafts. The investigators further find that typical parameters such as lactate, glucose and bile chemistry are poorly correlated with post-transplant outcomes.

Finally, the investigators have validated FMN measured in bile as an add on identifying biliary injury in both a binary and a quantitative sense, specifically predicting biliary complications with different clinical severity and need for interventions.

This is a multicenter observational validation study. It is estimated 850 that patients will be needed across 10-15 study sites to confirm FMN as a viability marker during NMP. Around 250 patients will be enrolled from Cleveland Clinic, both retrospectively and prospectively, from October 22, 2022 - December 31, 2027.

• The primary aim of this study is to confirm and validate the ability of Flavin Mononucleotide (FMN) as a marker of future graft viability. The investigators aim in total for 10 to 15 participating centers, both in the US and UK, utilizing back-to-base normothermic machine perfusion with the OrganOx metra device.

Primary Endpoint: Graft functionality up to 1-year post-transplant, as measured by perfusate FMN, bile FMN and perfusate + bile FMN correlation with graft viability (Primary Non-function (PNF), non-anastomotic stricture (NAS), other related graft loss - death censored).

Secondary Endpoints:

• Clinically significant non-anastomotic strictures (NAS requiring intervention).
• All biliary complications, including AS, NAS, bile leaks
• Clinically significant NAS leading to graft loss
• Number of interventions required per NAS
• Complications according to Clavien-Dindo grading and comprehensive Complications Index (CCI)
• Primary nonfunction (PNF), early allograft dysfunction (EAD)
• Hepatic artery thrombosis (HAT) and other vascular complications
• Acute kidney injury (AKI), renal replacement therapy (RRT)
• Acute cellular rejection, number of biopsies, number of rejection episodes and severity
• Graft loss, death censored graft loss, recipient death, times and causes

Conditions

Liver Transplant Disorder

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: OTHER

Study Groups

Recipients who receive deceased-donor liver transplant using machine perfusion with OrganOx metra

Normothermic perfusion using OrganOx metra. Can be from DBD or DCD donor.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Age >18 years
• Any graft type (DBD or DCD)
• Any underlying recipient disease (i.e., end stage, liver tumour)
• Any other donor risk factors and static cold storage time prior to NMP accepted by the participating center for transplantation in context of OrganOx metra use
• Patients undergoing primary deceased donor liver transplantation where back-to-base NMP is used (OrganOx metra) from July 15, 2025 to December 31, 2027. (CCF only)
• Patients who have undergone deceased donor liver transplantation where back-to-base NMP was used (OrganOx metra) from October 22, 2022 to July 14, 2025. (CCF only)

Exclusion Criteria

• Patients receiving a liver graft that is not perfused with OrganOx metra
• Pediatric recipients (<18years)
• Patients listed for super urgent liver transplantation due to acute liver failure
• Patients receiving combined organ transplant (heart+liver, lung+liver, liver+kidney, liver+intestine)
• Patients receiving living donor liver transplant or a split (or reduced) liver transplantation or a domino graft.
• Re-transplantations

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

Sponsors

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Andrea Schlegel

Director, Abdominal Transplant Research

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrea Schlegel, MD, MBA

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Mary Bilancini, MS

Role: CONTACT

bilancm@ccf.org

216-444-8983

Erlind Allkushi, BS

Role: CONTACT

allkuse2@ccf.org

216-444-0223

Facility Contacts

Andrea Schlegel, MD, MBA

Role: primary

schlega4@ccf.org

216-339-0741

Mary Bilancini, MS

Role: backup

bilancm@ccf.org

216-444-8983

Other Identifiers

25-839

Identifier Type: -

Identifier Source: org_study_id