Dual Hypothermic Oxygenated Machine Perfusion in Liver Transplantation Using Allografts From Donors After Brain Death

NCT04812054 | Unknown DMC

• 2 other identifiers: 1WB1/NCN62019/34/E/NZ5/00433
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a randomized study on the effects of hypothermic oxygenated machine perfusion in patients undergoing liver transplantations from donors after brain death with allocation of patients to either end-ischemic hypothermic oxygenated machine perfusion group (at least 2 hours of allograft perfusion at 12 degrees Celsius though hepatic artery and portal vein prior to implantation) or simple cold storage group in a 1:3 ratio. The primary outcome measure of the study will be model for early graft dysfunction (MEAF) score. A total number of 104 patients, including 26 in the hypothermic perfusion group and 78 in simple cold storage group will be included. Data on potential risk factors for worse allograft function and increased ischemia-reperfusion injury will be collected perioperatively. Circulating levels of proinflammatory cytokines (IL-2, IL-10, TNFα), nuclear damage (HMGB-1, 8-OHdG), serum activity of transaminases, gamma-glutamyl-transpeptidase, bilirubin concentration, and INR will be assessed in the perioperative period. Wedge allograft biopsies will be performed 90 minutes post-reperfusion to evaluate activation of innate immunity (TLR4), activation of endothelium (vWF, P-selectin), hepatocyte necrosis, hepatocyte apoptosis (TUNEL assay), ATP content, and oxidative damage (malondialdehyde content). Further, wedge biopsies will be performed at the end of simple cold storage and at the beginning and after two hours of perfusion to determine steatosis and ATP content. During the perfusion, perfusate samples will be periodically tested for lactate, sodium, and potassium concentration, CO2 partiall pressure, and flavin mononucleotide concentration. Patients will be closely monitored in the postoperative period for allograft function and secondary end-points: 2-year recipient and graft survival, 2-year incidence of biliary complications, and 90-day complication rate. Both groups will be compared with respect to the primary and secondary end-points, circulating levels of IL-2, IL-10, TNFα, HMGB-1, 8-OHdG, activity of transaminases and gamma-glutamyl-transpeptidase, and findings in post-reperfusion allograft biopsies. Further, changes of hepatic steatosis and hepatic ATP content during perfusion will be evaluated, and the results of perfusate analyses will be tested as predictors of allograft function in the post-transplant period.

Conditions

Liver Cirrhosis; Liver Tumor; Liver Transplant Failure and Rejection

Keywords

liver transplantation; machine perfusion; primary non-function

Outcome Measures

Primary Outcomes (1)

• Model for early graft dysfunction score

  Continuous measure of allograft function in the early period after liver transplantation, calculated using serum alanine transaminase (ALT) activity, international normalized ratio for prothrombin time (INR), and serum bilirubin concentration within 3 first postoperative days

  3 days

Secondary Outcomes (4)

• Recipient survival

  2 years

• Graft survival

  2 years

• Biliary complications

  2-years

• Postoperative complications

  90 days

Other Outcomes (7)

• Cytokine release in the perioperative period

  1 day

• Allograft ischemia-reperfusion injury

  90 minutes

• Hepatocyte apoptosis in the allograft

  90 minutes

Study Arms (2)

Hypothermic oxygenated machine perfusion

EXPERIMENTAL

Allografts will be subject to end-ischemic hypothermic oxygenated perfusion at 12 degrees Celsius through both hepatic artery and portal vein after a period of simple cold storage at 4 degrees Celsius and immediately prior to implantation. The perfusion will last at least 2 hours and the period will be prolonged in case of ongoing hepatectomy, in order to perform graft implantation immediately after perfusion.

Procedure: Hypothermic oxygenated machine perfusion

Simple cold storage

ACTIVE COMPARATOR

Allografts will be stored in perfusate at 4 degrees Celsius from the procurement until implantation.

Procedure: Simple cold storage

Interventions

Hypothermic oxygenated machine perfusion PROCEDURE

Hypothermic oxygenated perfusion using a Liver Assist device (Organ Assist, Groningen, the Netherlands). Temperature of the perfusate will be set to 12 degrees Celsius. Dedicated cannulas will be placed in the aorta for arterial perfusion and in the portal vein for portal perfusion. Pressure will be set at 25 mmHg for arterial line (pulsatile flow, 30 mmHg systolic pressure and 20 mmHg diastolic pressure, 60 beats per minute) and 3 mmHg for portal line (continuous flow). 100% oxygen will be supplied to the oxygenators with a flow of 500 ml / min or higher, in order to achieve pO2 of at least 450 mmHg.

Also known as: DHOPE

Hypothermic oxygenated machine perfusion

Simple cold storage PROCEDURE

Following back-table preparation, the allograft will either be transferred to the operating room for implantation or stored in preservation solution at 4 degrees Celsius in a refrigerator

Simple cold storage

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age \>18 years
• deceased-donor liver transplantation
• provision of informed consent

You may not qualify if:

• donation after cardiac death
• either reduced or split graft

Sponsors & Collaborators

• Medical University of Warsaw: lead
• National Science Centre, Poland: collaborator

Study Sites (1)

Department of General, Transplant and Liver Surgery, Medical University of Warsaw

Warsaw, Masovian Voivodeship, 02-097, Poland

RECRUITING

Related Publications (1)

• Grat M, Morawski M, Zhylko A, Rykowski P, Krasnodebski M, Wyporski A, Borkowski J, Lewandowski Z, Kobryn K, Stankiewicz R, Stypulkowski J, Holowko W, Patkowski W, Mielczarek-Puta M, Struga M, Szczepankiewicz B, Gornicka B, Krawczyk M. Routine End-ischemic Hypothermic Oxygenated Machine Perfusion in Liver Transplantation From Donors After Brain Death: A Randomized Controlled Trial. Ann Surg. 2023 Nov 1;278(5):662-668. doi: 10.1097/SLA.0000000000006055. Epub 2023 Jul 27.

  PMID: 37497636 DERIVED

MeSH Terms

Conditions

Liver Cirrhosis; Carcinoma, Hepatocellular; Rejection, Psychology

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Social Behavior; Behavior

Study Officials

• Michal Grat, MD, PhD

  Medical University of Warsaw

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michal Grat, MD, PhD

CONTACT

0048225992545; michal.grat@wum.edu.pl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Following provision of informed consent, recipients will be randomly assigned in a 1:3 ratio to either hypothermic perfusion group or simple static cold storage group. Randomization will be performed in the blocks of 8 by drawing a sealed envelope by the investigator immediately after organ procurement.

Study Record Dates

• First Submitted: March 16, 2021
• First Posted: March 23, 2021
• Study Start: April 5, 2021
• Primary Completion: April 1, 2022
• Study Completion: April 1, 2024
• Last Updated: April 13, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be available from the investigators upon reasonable request following the publication of final article reporting on all primary and secondary outcome measures
• Access Criteria: Requests should be addressed to the principal investigator

Locations

PL (1)