Establishing a Reference Framework for Outcomes After Machine-Preserved Liver Transplantation in Europe (REFRAME-MP)

Establishing a Reference Framework for Outcomes After Machine-Preserved Liver Transplantation in Europe (REFRAME-MP)

Machine perfusion (MP) has become routine clinical practice in liver transplantation. However, as the field has matured, direct randomized comparisons between distinct MP modalities have become increasingly impractical, given that donor and graft characteristics often predetermine the optimal preservation strategy. Consequently, many studies continue to reference historical benchmark cohorts from the pre-perfusion era, or use risk scores developed before routine utilization of MP. These cohorts, while once valuable, fail to account for the paradigm shift that MP has introduced. Likewise, commonly used donor- and recipient-based risk scores were developed prior to the adoption of MP. While these scores aim to assess survival or morbidity after transplantation, none of them guide decisions about MP use or the most suitable perfusion protocol. As MP technologies continue to evolve there is a critical need for an updated reference framework that accurately reflects current clinical practice and captures the best achievable outcomes across all MP modalities.

Study Overview

• Status: Recruiting
• Conditions: Liver Transplantation; Liver Cirrhosis; Acute Liver Failure; End-stage Liver Disease (ESLD)
• Intervention / Treatment: Device: Endischemic hypothermic oxygenated machine perfusion (any device); Device: Endischemic (back-to-base) normothermic machine perfusion (any device); Device: Continuous (device-to-donor) normothermic machine perfusion (any device); Device: Endischemic HOPE-COR-NMP (any device); Device: Endischemic HOPE-NMP (any device); Device: Normothermic regional perfusion (any device); Other: Static cold storage

Detailed Description

The aim of this study is to establish a reference framework for liver transplantation outcomes in the era of routine clinical machine perfusion. In addition, based on the collected real-world observational data, a target trial emulation approach will be applied.

• Study Type: Observational
• Enrollment (Estimated): 10000

Contacts and Locations

• Study Contact: Name: Sabrina Stimmeder, MD; Phone Number: +31503612896‬; Email: s.stimmeder@umcg.nl

Study Locations

• Italy
  • Torino, Italy
    • Recruiting
    • A.O.U. Città della Salute e della Scienza
    • Contact: Damiano Patrono, MD, PhD
• Netherlands
  • Provincie Groningen
    • Groningen, Provincie Groningen, Netherlands
      • Recruiting
      • University Medical Center Groningen
      • Principal Investigator: Vincent E de Meijer, MD, PhD
      • Contact: Sabrina Stimmeder, MD; Phone Number: +31503612896‬; Email: s.stimmeder@umcg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All postmortal livers accepted (transplanted and not-transplanted after machine perfusion) upon organ offer between 01.01.2021 and 31.12.2025 for patients >18 years at the time of liver transplantation.

Description

Inclusion Criteria:

• All postmortal livers accepted (transplanted and not-transplanted after machine perfusion) upon organ offer for patients >18 years at the time of liver transplantation.
• All donor types (DBD, DCD)
• Preservation either with static cold storage alone or combined with machine perfusion (MP).
• Donor livers underwent MP as part of routine clinical practice and the choice of perfusion protocol was made according to institutional standard practice.

• Eligible MP protocols are:

  1. end-ischemic single- or dual hypothermic oxygenated MP [e(D)HOPE],
  2. end-ischemic (back-to-base) normothermic MP [eNMP],
  3. continuous (device-to-donor) normothermic MP [cNMP],
  4. e(D)HOPE followed by controlled oxygenated rewarming and normothermic MP [e(D)HOPE-COR-NMP)],
  5. e(D)HOPE followed by normothermic MP [e(D)HOPE-NMP], or
  6. Normothermic regional perfusion followed by SCS or an ex situ MP protocol.
• A minimum follow-up of 12 months after liver transplantation is required.

Exclusion Criteria:

• Livers that were allocated to a MP protocol as part of a prospective randomized or interventional clinical trial comparing different preservation techniques or any other invention.
• Living donor liver transplantation

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death-censored graft survival	Defined as the time from liver transplantation until re-transplantation or death due to graft failure (analyzed using time-to-event methods).	Actuarial survival 1-5 year post-transplantation
Overall patient survival	Defined as time from liver transplantation until re-transplantation or all-cause death (analyzed using time-to-event methods).	Actuarial survival 1-5 year post-transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall graft survival	Defined as time from liver transplantation until re-transplantation or all-cause death (analyzed using time-to-event methods)	Actuarial survival 1-5 year post-transplantation
Incidence of major liver-related complications	Incidence of at least one biliary or vascular complication graded as Clavien-Dindo IIIb or higher, following the grading recommendations published: de Goeij FHC, Wehrle CJ, Abbassi F, et al. Mastering the narrative: Precision reporting of risk and outcomes in liver transplantation. J Hepatol. 2025;82(4):729-743. doi:10.1016/j.jhep.2024.11.013. Additionally, scoring accoring the Comprehensive Complication Index.	within the transplant-related admission, and 1 year post-transplantation
Incidence of graft loss due to complications	Graft loss as a result of complications assessed separately for biliary complications, vascular complications, and rejection.	within 1 year post-transplantation, up to 5 years post-transplantation
Total number of clinically significant biliary complications	Total number of any biliary complications requiring interventions (Clavien-Dindo grade IIIa or higher).	within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of biliary complications	Biliary complications include: Post-transplant cholangiopathy; Anastomotic strictures; Biliary leakage	within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of vascular complications	Vascular complications include: Hepatic artery thrombosis; Portal vein thrombosis; Venous outflow tract obstruction	within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of re-transplantation	Re-transplantation for any cause.	within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of acute rejection		within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of chronic rejection		within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of recurrence of primary disease	Histologically or radiologically confirmed recurrence, including recurrence of malignancies	within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of kidney injury	Kidney injury includes: Acute kidney injury; New-onset chronic kidney disease	within 1 year post-transplantation, up to 5 years post-transplantation
Incidence of primary non-function	Liver graft failure within the first 7 days of transplantation with patent liver vessels leading to re-transplantation or patient death	up to 1 week post-transplantation
Patient-centered outcomes (measure of recovery and healthcare utilization)	Length of intensive care unit stay and length of initial hospital stay (starting at day of transplantation until day of discharge, measured in days)	within 1 year post-transplantation

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: A.O.U. Città della Salute e della Scienza
• Investigators: Principal Investigator: Vincent E de Meijer, MD, PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: May 11, 2026
• First Posted (Actual): May 14, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: liver transplantation; organ preservation; normothermic machine perfusion; hypothermic machine perfusion; machine perfusion; machine preservation; normothermic regional perfusion
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Fibrosis; Pathological Conditions, Signs and Symptoms; Liver Cirrhosis; End Stage Liver Disease; Liver Failure, Acute
• Other Study ID Numbers: UMCG_REFRAME-MP; METc 2026/180 (Registry Identifier: UMCG METc number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No