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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Liver Failure, End Stage Liver Disease, Biliary Tract Diseases

Intervention / Treatment
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* Procedure: Dual hypothermic oxygenated perfusion
* Device: Liver Assist®
* Procedure: Perfusion fluid
* Drug: Glutathione


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Transplantation, Donation after Circulatory Death, Machine Perfusion