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

Phase 3

Completed

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

• Registration Number: NCT02584283
• Lead Sponsor: Robert J. Porte

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-09-25
• Study First Submitted QC: 2015-10-20
• Study First Posted: 2015-10-22
• Study Start: 2016-01
• Primary Completion: 2020-01
• Study Completion: 2020-01
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-08
• Last Update Posted: 2021-01-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 157

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dual hypothermic oxygenated perfusion	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.
Dual hypothermic oxygenated perfusion	Liver Assist®	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.
Dual hypothermic oxygenated perfusion	Perfusion fluid	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.
Dual hypothermic oxygenated perfusion	Glutathione	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.

Primary Outcome Measures

Name	Time	Method
The incidence of symptomatic non-anastomotic biliary strictures (NAS)	6 months	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

Secondary Outcome Measures

Name	Time	Method
Asymptomatic NAS	6 months	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
The severity of NAS	6 months	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)
The location of NAS	6 months	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.
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	7 days	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
Initial poor function	7 days	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
Biochemical analysis of graft function and ischemia-reperfusion injury	Postoperative day 0 - 7 and 1, 3, 6 months	serum levels of alanine aminotransferase (ALT), AST, alkaline phosphatase (AlkP), gamma-glutamyl transferase (γGT), and total bilirubin
Blood pressure	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion	mm Hg
Heart rate	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion	beats per minute
Vasopressor dosage	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion	microgram/kg/min
Length of stay	6 months	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
Postoperative complications	6 months	According to the comprehensive complication index (CCI)
Renal function	day 7, and 1, 3, 6 months	Estimated glomerular filtration rate (eGFR) according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation
Flow	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion	ml/min
Pressure	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion	mm Hg
Resistance	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion	ml/min/mm Hg
(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	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	mmol/L
(In selected centers) value of perfusate's potassium	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	mmol/L
(In selected centers) value of perfusate's bicarbonate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	mmol/l
(In selected centers) value of perfusate's lactate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	mmol/l
(In selected centers) value of perfusate's alanine transaminase (ALT)	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	U/L
(In selected centers) value of perfusate's aspartate transaminase (AST)	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	U/L
(In selected centers) value of perfusate's alkaline phosphatase (AlkP)	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	U/L
(In selected centers) value of perfusate's gamma glutamyltransferase (γGT)	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	U/L
(In selected centers) value of perfusate's urea	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	mmol/L
(In selected centers) value of perfusate's total bilirubin	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	umol/l
(In selected centers) value of perfusate's thrombomodulin	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	pg/dl
(In selected centers) value of perfusate's high mobility group box-1 (HMBG) protein	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	μg/mL
(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	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	relative levels compared to perfusate
(In selected centers) level of miRNA CDmiR-222 in perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	relative levels compared to perfusate
(In selected centers) level of miRNA CDmiR-296 in perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	relative levels compared to perfusate
(In selected centers) level of miRNA HDmiR-122 in perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	relative levels compared to perfusate
(In selected centers) level of miRNA HDmiR-148a in perfusate	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion	relative levels compared to perfusate
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	90 days	* 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.
Costs of treatment (in selected centers)	within 6 months after transplantation, including transplant operation	according to the Cost and Outcome analysis of Liver Transplantation (COLT) study
Health related quality of life	within 6 months before transplantation and 6 months after transplantation	EQ6D questionnaire

Trial Locations

Locations (6)

Ghent University Hospital; 🇧🇪 Gent, De Pintelaan 185, Belgium

Leiden Universtiy Medical Center; 🇳🇱 Leiden, Zuid-Holland, Netherlands

University Hospitals Leuven; 🇧🇪 Leuven, Herestraat 49, Belgium

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands

Erasmus Medical Center; 🇳🇱 Rotterdam, Netherlands

King's College Hospital NHS Trust; 🇬🇧 London, United Kingdom