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

Liver Failure Clinical Trial

— DHOPE-DCD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02584283
• Other study ID #: DHOPE-DCD Trial
• Status: Completed
• Phase: Phase 3
• Start date: January 2016
• Est. completion date: January 2020

Study information

• Verified date: January 2021
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 157
• Est. completion date: January 2020
• Est. primary completion date: January 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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)

Related Conditions & MeSH terms

• Biliary Tract Diseases
• End Stage Liver Disease
• Liver Diseases
• Liver Failure

Intervention

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.

Locations

Country	Name	City	State
Belgium	Ghent University Hospital	Gent	De Pintelaan 185
Belgium	University Hospitals Leuven	Leuven	Herestraat 49
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden Universtiy Medical Center	Leiden	Zuid-Holland
Netherlands	Erasmus Medical Center	Rotterdam
United Kingdom	King's College Hospital NHS Trust	London

Sponsors (6)

Lead Sponsor	Collaborator
Robert J. Porte	Erasmus Medical Center, King's College Hospital NHS Trust, Leiden University Medical Center, Universitaire Ziekenhuizen Leuven, University Hospital, Ghent

Countries where clinical trial is conducted

Belgium,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Graft (censored and uncensored for patient death) survival		7 days, 1, 3 , 6, and 12 months after transplantation
Secondary	Patient survival		7 days, 1, 3 , 6, and 12 months after transplantation
Secondary	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
Secondary	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
Secondary	Biochemical analysis of graft function and ischemia-reperfusion injury	serum levels of alanine aminotransferase (ALT), AST, alkaline phosphatase (AlkP), gamma-glutamyl transferase (?GT), and total bilirubin	Postoperative day 0 - 7 and 1, 3, 6 months
Secondary	Blood pressure	mm Hg	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Secondary	Heart rate	beats per minute	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Secondary	Vasopressor dosage	microgram/kg/min	5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
Secondary	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
Secondary	Postoperative complications	According to the comprehensive complication index (CCI)	6 months
Secondary	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
Secondary	Flow	ml/min	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Secondary	Pressure	mm Hg	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Secondary	Resistance	ml/min/mm Hg	At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(In selected centers) value of perfusate's gamma glutamyltransferase (?GT)	U/L	At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	(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
Secondary	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
Secondary	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
Secondary	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
Secondary	Health related quality of life	EQ6D questionnaire	within 6 months before transplantation and 6 months after transplantation