Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation

NCT02584283 | Completed Phase 3 DMC

• 1 other identifier: DHOPE-DCD Trial
• Study Type: interventional
• Target: 157
• Locations: 3 countries
• Sites: 6

Brief Summary

Rationale: Recent publications report good results of controlled donation after circulatory death (DCD) Maastricht category III liver transplantation when strict donor-recipient matching is applied and ischemia times are kept to a minimum. However a major concern remains the high rate of biliary complications after transplantation of DCD livers. Non-anastomotic biliary strictures (NAS) occur in 29% of patients receiving a DCD graft whereas the incidence of NAS in recipients of donation after brain death (DBD) liver grafts is 11%. NAS are associated with higher morbidity and increased cost of liver transplantation. Injury to the biliary epithelium and the peribiliary vascular plexus occurring during donor warm ischemia and static cold storage (SCS) has been identified as a major risk factor for development of NAS. Machine perfusion has been proposed as an alternative strategy for organ preservation, offering the opportunity to improve the quality of the organ by providing oxygen to the graft. Experimental studies have shown that end-ischemic dual hypothermic oxygenated machine perfusion (DHOPE) helps liver grafts to recover from ischemia by restoring mitochondrial function. Moreover, DHOPE has been shown to provide better preservation of peribiliary vascular plexus of the bile ducts, which could be an important step forward in reducing the incidence of NAS after transplantation. Objective: To study the efficacy of end-ischemic DHOPE in reducing the incidence of NAS within six months after controlled DCD (Maastricht category III) liver transplantation. Study design: An international, multicenter, prospective, randomized, controlled, interventional, clinical trial with a two parallel arm approach (treatment/control). Study population: Adult patients (≥18 yrs old) undergoing a liver transplantation with a liver graft procured from a controlled DCD donor (Maastricht category III) with a body weight ≥40 kg. Intervention: In the intervention group liver grafts will be subjected to two hours of hypothermic, oxygenated perfusion at the end of SCS and before implantation. In the control group donor liver grafts will be preserved in accordance to standard practice by SCS only. Main study parameters/endpoints: The incidence and severity of symptomatic NAS as diagnosed by an Adjudication committee (who are blinded for the group assignment) by means of magnetic resonance cholangiopancreatography (MRCP).

Conditions

Liver Failure; End Stage Liver Disease; Biliary Tract Diseases

Keywords

Liver Transplantation; Donation after Circulatory Death; Machine Perfusion

Outcome Measures

Primary Outcomes (1)

• The incidence of symptomatic non-anastomotic biliary strictures (NAS)

  NAS is defined as all of the following criteria: * any irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis * which are diagnosed by cholangiogram (preferably by MRCP) * in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography * and as assessed by the Adjudication Committee * when imaging is indicated by clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up

  6 months

Secondary Outcomes (40)

• Asymptomatic NAS

  6 months

• The severity of NAS

  6 months

• The location of NAS

  6 months

• Graft (censored and uncensored for patient death) survival

  7 days, 1, 3 , 6, and 12 months after transplantation

• Patient survival

  7 days, 1, 3 , 6, and 12 months after transplantation

Study Arms (2)

Dual hypothermic oxygenated perfusion

EXPERIMENTAL

The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.

Procedure: Dual hypothermic oxygenated perfusion; Device: Liver Assist®; Procedure: Perfusion fluid; Drug: Glutathione

Care as usual

NO INTERVENTION

The donor liver is procured with a segment of 5 cm circular supratruncal aorta left attached to the coeliac trunc. The patients randomized to the control group will receive a liver graft preserved by conventional SCS without any further intervention.

Interventions

Dual hypothermic oxygenated perfusion PROCEDURE

Dual hypothermic oxygenated perfusion using the Liver Assist

Dual hypothermic oxygenated perfusion

Liver Assist® DEVICE

The Liver Assist® is the device used to give the intervention dual hypothermic perfusion.

Dual hypothermic oxygenated perfusion

Perfusion fluid PROCEDURE

The perfusion fluid is Belzer machine perfusion solution University of Wisconsin (Bridge-to-Life, Ltd., Northbrook, IL).

Dual hypothermic oxygenated perfusion

Glutathione DRUG

Glutathione in a dosage of 3 mmol/ is added to the perfusion fluid according to the intention of use of the perfusion fluid.

Dual hypothermic oxygenated perfusion

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (≥ 18 years old)
• Signed informed consent
• Willing and able to attend follow-up examinations
• Donor liver graft from a controlled donation after circulatory death (Maastricht category III)
• Donors with a body weight ≥40 kg

You may not qualify if:

• Simultaneous participation in another clinical trial that might possibly influence this trial
• Mental conditions rendering the subject incapable to understand the nature, scope and consequences of the trial
• Listed for liver transplantation due to fulminant liver failure or retransplantation because of primary non-function
• Recipient positive test for HIV
• Donor positive for HIV antigen, hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody
• Simultaneous transplantation of another organ
• Patients with contra-indications for MRCP (i.e. pacemaker)

Sponsors & Collaborators

• Robert J. Porte: lead
• Erasmus Medical Center: collaborator
• Leiden University Medical Center: collaborator
• Universitaire Ziekenhuizen KU Leuven: collaborator
• University Hospital, Ghent: collaborator
• King's College Hospital NHS Trust: collaborator

Study Sites (6)

Ghent University Hospital

Ghent, De Pintelaan 185, 9000, Belgium

Location

University Hospitals Leuven

Leuven, Herestraat 49, 3000, Belgium

Location

Leiden Universtiy Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

Location

University Medical Center Groningen

Groningen, 9700 RB, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3015 CE, Netherlands

Location

King's College Hospital NHS Trust

London, United Kingdom

Location

Related Publications (5)

• van Rijn R, Endo C, Kucukerbil EH, Blokzijl H, Blondeel J, Cortes Cerisuelo M, Coenraad MJ, Darwish Murad S, Doukas M, Eker H, de Haas RJ, Huurman VAL, de Meijer VE, Monbaliu D, Schurink IJ, Slangen JJG, Polak WG, de Jonge J, Porte RJ. Long-term Follow-up After Hypothermic Oxygenated Machine Perfusion in DCD Liver Transplantation: Results of a Randomized Controlled Multicenter Trial (DHOPE-DCD). Ann Surg. 2025 Nov 1;282(5):717-724. doi: 10.1097/SLA.0000000000006876. Epub 2025 Aug 5.

  PMID: 41082480 DERIVED

• Endo C, van Rijn R, Huurman V, Schurink I, van den Berg A, Murad SD, van Hoek B, de Meijer VE, de Jonge J, van der Hilst CS, Porte RJ. Cost-effectiveness of Dual Hypothermic Oxygenated Machine Perfusion Versus Static Cold Storage in DCD Liver Transplantation. Transplantation. 2025 Feb 1;109(2):e101-e108. doi: 10.1097/TP.0000000000005232. Epub 2024 Oct 8.

  PMID: 39853733 DERIVED

• van Rijn R, Schurink IJ, de Vries Y, van den Berg AP, Cortes Cerisuelo M, Darwish Murad S, Erdmann JI, Gilbo N, de Haas RJ, Heaton N, van Hoek B, Huurman VAL, Jochmans I, van Leeuwen OB, de Meijer VE, Monbaliu D, Polak WG, Slangen JJG, Troisi RI, Vanlander A, de Jonge J, Porte RJ; DHOPE-DCD Trial Investigators. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. N Engl J Med. 2021 Apr 15;384(15):1391-1401. doi: 10.1056/NEJMoa2031532. Epub 2021 Feb 24.

  PMID: 33626248 DERIVED

• de Vries Y, Berendsen TA, Fujiyoshi M, van den Berg AP, Blokzijl H, de Boer MT, van der Heide F, de Kleine RHJ, van Leeuwen OB, Matton APM, Werner MJM, Lisman T, de Meijer VE, Porte R. Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJ Open. 2019 Aug 15;9(8):e028596. doi: 10.1136/bmjopen-2018-028596.

  PMID: 31420387 DERIVED

• van Rijn R, van den Berg AP, Erdmann JI, Heaton N, van Hoek B, de Jonge J, Leuvenink HGD, Mahesh SVK, Mertens S, Monbaliu D, Muiesan P, Perera MTPR, Polak WG, Rogiers X, Troisi RI, de Vries Y, Porte RJ. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol. 2019 Mar 12;19(1):40. doi: 10.1186/s12876-019-0956-6.

  PMID: 30866837 DERIVED

MeSH Terms

Conditions

Liver Failure; End Stage Liver Disease; Biliary Tract Diseases

Interventions

newcastle organ perfusion fluid; Glutathione

Condition Hierarchy (Ancestors)

Hepatic Insufficiency; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Robert J. Porte, MD PhD Prof

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. dr.

Study Record Dates

• First Submitted: September 25, 2015
• First Posted: October 22, 2015
• Study Start: January 1, 2016
• Primary Completion: January 1, 2020
• Study Completion: January 1, 2020
• Last Updated: January 12, 2021

Record last verified: 2021-01

Locations

NL (3); BE (2); GB (1)