Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation (DHOPE-DCD)

A Multicenter Randomized Controlled Trial to Compare the Efficacy of End-ischemic Dual Hypothermic Oxygenated Perfusion With Standard Static Cold Storage of Liver Grafts Donated After Circulatory Death in Preventing Biliary Complications

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).

Study Overview

• Status: Completed
• Conditions: End Stage Liver Disease; Liver Failure; Biliary Tract Diseases
• Intervention / Treatment: Procedure: Dual hypothermic oxygenated perfusion; Device: Liver Assist®; Procedure: Perfusion fluid; Drug: Glutathione

• Study Type: Interventional
• Enrollment (Actual): 157
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • De Pintelaan 185
    • Gent, De Pintelaan 185, Belgium, 9000
      • Ghent University Hospital
  • Herestraat 49
    • Leuven, Herestraat 49, Belgium, 3000
      • University Hospitals Leuven
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus Medical Center
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands, 2333 ZA
      • Leiden Universtiy Medical Center
• United Kingdom
  • London, United Kingdom
    • King's College Hospital NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Procedure: Dual hypothermic oxygenated perfusion; Dual hypothermic oxygenated perfusion using the Liver Assist; Device: Liver Assist®; The Liver Assist® is the device used to give the intervention dual hypothermic perfusion.; Procedure: Perfusion fluid; The perfusion fluid is Belzer machine perfusion solution University of Wisconsin (Bridge-to-Life, Ltd., Northbrook, IL).; Drug: Glutathione; Glutathione in a dosage of 3 mmol/ is added to the perfusion fluid according to the intention of use of the perfusion fluid.
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Asymptomatic NAS	Asymptomatic NAS is defined as all of the following: 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; in the absence of clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up	6 months
The severity of NAS	Severity and location of NAS is based on assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al. And required treatment for NAS (i.e. ursodeoxycholic acid, ERCP, retransplantation)	6 months
The location of NAS	Assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al.	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
Primary non-function	Defined as liver failure requiring retransplantation or leading to death within seven days after transplantation without any identifiable cause such as surgical problems, hepatic artery thrombosis, portal vein thrombosis and acute rejection	7 days
Initial poor function	Defined as a modification of the Olthoff criteria: Prothrombin time/ international normalized ratio (INR) >1.6 and or serum total bilirubin >10 mg/dL on postoperative day 7	7 days
Biochemical analysis of graft function and ischemia-reperfusion injury	serum levels of alanine aminotransferase (ALT), AST, alkaline phosphatase (AlkP), gamma-glutamyl transferase (γGT), and total bilirubin	Postoperative day 0 - 7 and 1, 3, 6 months
Blood pressure	mm Hg	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Heart rate	beats per minute	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Vasopressor dosage	microgram/kg/min	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Length of stay	Length of initial ICU and initial hospital stay is determined in days of admission following liver transplantation. Duration of follow-up hospital stay is determined in days of hospital admission after discharge and up to six months after liver transplantation	6 months
Postoperative complications	According to the comprehensive complication index (CCI)	6 months
Renal function	Estimated glomerular filtration rate (eGFR) according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation	day 7, and 1, 3, 6 months
Flow	ml/min	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Pressure	mm Hg	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Resistance	ml/min/mm Hg	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
(In selected centers) value of perfusate's pH		At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's sodium	mmol/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's potassium	mmol/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's bicarbonate	mmol/l	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's lactate	mmol/l	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's alanine transaminase (ALT)	U/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's aspartate transaminase (AST)	U/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's alkaline phosphatase (AlkP)	U/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's gamma glutamyltransferase (γGT)	U/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's urea	mmol/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's total bilirubin	umol/l	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's thrombomodulin	pg/dl	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's high mobility group box-1 (HMBG) protein	μg/mL	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) value of perfusate's cytochrome C		At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA CDmiR-30e in perfusate	relative levels compared to perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA CDmiR-222 in perfusate	relative levels compared to perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA CDmiR-296 in perfusate	relative levels compared to perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA HDmiR-122 in perfusate	relative levels compared to perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
(In selected centers) level of miRNA HDmiR-148a in perfusate	relative levels compared to perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
Histopathological status liver and bile ducts (in selected centers)		Within 0 to 30 minutes before perfusion, at 2 hours of perfusion, and at 1 hour after reperfusion
New onset diabetes after transplantation	Symptoms of diabetes and random plasma glucose ≥11.1 mmol/L. Symptoms include polyuria, polydipsia, and unexplained weight loss. OR; Fasting plasma glucose ≥7.0 mmol/L. Fasting is defined as no caloric intake for at least eight hours. OR; Two-hour plasma glucose ≥11.1 mmol/L during an oral glucose tolerance test. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.	90 days
Costs of treatment (in selected centers)	according to the Cost and Outcome analysis of Liver Transplantation (COLT) study	within 6 months after transplantation, including transplant operation
Health related quality of life	EQ6D questionnaire	within 6 months before transplantation and 6 months after transplantation

Collaborators and Investigators

• Sponsor: Robert J. Porte
• Collaborators: King's College Hospital NHS Trust; Universitaire Ziekenhuizen KU Leuven; Erasmus Medical Center; University Hospital, Ghent; Leiden University Medical Center
• Investigators: Principal Investigator: Robert J. Porte, MD PhD Prof, University Medical Center Groningen

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: September 25, 2015
• First Submitted That Met QC Criteria: October 20, 2015
• First Posted (Estimate): October 22, 2015

Study Record Updates

• Last Update Posted (Actual): January 12, 2021
• Last Update Submitted That Met QC Criteria: January 8, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Liver Transplantation; Machine Perfusion; Donation after Circulatory Death
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Liver Diseases; End Stage Liver Disease; Liver Failure; Biliary Tract Diseases
• Other Study ID Numbers: DHOPE-DCD Trial