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NCT Number: NCT02584283

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

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).

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Key information

Conditions

Liver Failure Biliary Tract Diseases Digestive System Diseases End Stage Liver Disease Hepatic Insufficiency Liver Diseases

Age range

18 year–100 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Ghent University Hospital, Ghent, De Pintelaan 185, Belgium

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Dual hypothermic oxygenated perfusion

Procedure

Dual hypothermic oxygenated perfusion using the Liver Assist

Liver Assist®

Device

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

Perfusion fluid

Procedure

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

Glutathione

Drug

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

Primary outcomes

  1. The incidence of symptomatic non-anastomotic biliary strictures (NAS)

    Time frame: 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 outcomes

  1. Asymptomatic NAS

    Time frame: 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

  2. The severity of NAS

    Time frame: 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)

  3. The location of NAS

    Time frame: 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.

  4. Graft (censored and uncensored for patient death) survival

    Time frame: 7 days, 1, 3 , 6, and 12 months after transplantation

  5. Patient survival

    Time frame: 7 days, 1, 3 , 6, and 12 months after transplantation

  6. Primary non-function

    Time frame: 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

  7. Initial poor function

    Time frame: 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

  8. Biochemical analysis of graft function and ischemia-reperfusion injury

    Time frame: 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

  9. Blood pressure

    Time frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion

    mm Hg

  10. Heart rate

    Time frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion

    beats per minute

  11. Vasopressor dosage

    Time frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion

    microgram/kg/min

  12. Length of stay

    Time frame: 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

  13. Postoperative complications

    Time frame: 6 months

    According to the comprehensive complication index (CCI)

  14. Renal function

    Time frame: 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

  15. Flow

    Time frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion

    ml/min

  16. Pressure

    Time frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion

    mm Hg

  17. Resistance

    Time frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion

    ml/min/mm Hg

  18. (In selected centers) value of perfusate's pH

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

  19. (In selected centers) value of perfusate's sodium

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    mmol/L

  20. (In selected centers) value of perfusate's potassium

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    mmol/L

  21. (In selected centers) value of perfusate's bicarbonate

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    mmol/l

  22. (In selected centers) value of perfusate's lactate

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    mmol/l

  23. (In selected centers) value of perfusate's alanine transaminase (ALT)

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    U/L

  24. (In selected centers) value of perfusate's aspartate transaminase (AST)

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    U/L

  25. (In selected centers) value of perfusate's alkaline phosphatase (AlkP)

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    U/L

  26. (In selected centers) value of perfusate's gamma glutamyltransferase (γGT)

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    U/L

  27. (In selected centers) value of perfusate's urea

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    mmol/L

  28. (In selected centers) value of perfusate's total bilirubin

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    umol/l

  29. (In selected centers) value of perfusate's thrombomodulin

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    pg/dl

  30. (In selected centers) value of perfusate's high mobility group box-1 (HMBG) protein

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

    μg/mL

  31. (In selected centers) value of perfusate's cytochrome C

    Time frame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion

  32. (In selected centers) level of miRNA CDmiR-30e in perfusate

    Time frame: 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

  33. (In selected centers) level of miRNA CDmiR-222 in perfusate

    Time frame: 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

  34. (In selected centers) level of miRNA CDmiR-296 in perfusate

    Time frame: 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

  35. (In selected centers) level of miRNA HDmiR-122 in perfusate

    Time frame: 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

  36. (In selected centers) level of miRNA HDmiR-148a in perfusate

    Time frame: 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

  37. Histopathological status liver and bile ducts (in selected centers)

    Time frame: Within 0 to 30 minutes before perfusion, at 2 hours of perfusion, and at 1 hour after reperfusion

  38. New onset diabetes after transplantation

    Time frame: 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.

  39. Costs of treatment (in selected centers)

    Time frame: within 6 months after transplantation, including transplant operation

    according to the Cost and Outcome analysis of Liver Transplantation (COLT) study

  40. Health related quality of life

    Time frame: within 6 months before transplantation and 6 months after transplantation

    EQ6D questionnaire

Sponsors and collaborators

Lead sponsor

Robert J. Porte

Other

Collaborators

  • Erasmus Medical Center
  • King's College Hospital NHS Trust
  • Leiden University Medical Center
  • Universitaire Ziekenhuizen KU Leuven
  • University Hospital, Ghent

Registry information

Official study 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

Acronym: DHOPE-DCD

Important dates

Study start
2016
Primary completion
2020
Study completion
2020
First posted
Oct 22, 2015
Registry last updated
Jan 12, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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