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

NCT ID: NCT02584283

Last Updated: 2021-01-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 157 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2020-01-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Dual hypothermic oxygenated perfusion

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.

Group Type: EXPERIMENTAL

Dual hypothermic oxygenated perfusion

Intervention Type: PROCEDURE

Dual hypothermic oxygenated perfusion using the Liver Assist

Liver Assist®

Intervention Type: DEVICE

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

Perfusion fluid

Intervention Type: PROCEDURE

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

Glutathione

Intervention Type: DRUG

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

Care as usual

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Dual hypothermic oxygenated perfusion

Dual hypothermic oxygenated perfusion using the Liver Assist

Intervention Type: PROCEDURE

Liver Assist®

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

Intervention Type: DEVICE

Perfusion fluid

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

Intervention Type: PROCEDURE

Glutathione

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Erasmus Medical Center

OTHER

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: collaborator

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role: collaborator

University Hospital, Ghent

OTHER

Sponsor Role: collaborator

King's College Hospital NHS Trust

OTHER

Sponsor Role: collaborator

Robert J. Porte

OTHER

Sponsor Role: lead

Responsible Party

Robert J. Porte

Prof. dr.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Robert J. Porte, MD PhD Prof

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

Ghent University Hospital

Ghent, De Pintelaan 185, Belgium

University Hospitals Leuven

Leuven, Herestraat 49, Belgium

Leiden Universtiy Medical Center

Leiden, South Holland, Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

King's College Hospital NHS Trust

London, , United Kingdom

Countries

Belgium; Netherlands; United Kingdom

References

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Reference Type: DERIVED

PMID: 41082480 (View on PubMed)

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.

Reference Type: DERIVED

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Reference Type: DERIVED

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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.

Reference Type: DERIVED

PMID: 31420387 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30866837 (View on PubMed)

Other Identifiers

DHOPE-DCD Trial

Identifier Type: -

Identifier Source: org_study_id