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

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ClinicalTrials.gov Identifier: NCT02584283
Recruitment Status : Recruiting
First Posted : October 22, 2015
Last Update Posted : December 20, 2018
Sponsor:
Collaborators:
Erasmus Medical Center
Leiden University Medical Center
Information provided by (Responsible Party):
Robert J. Porte, University Medical Center Groningen

Tracking Information
First Submitted Date  ICMJE September 25, 2015
First Posted Date  ICMJE October 22, 2015
Last Update Posted Date December 20, 2018
Study Start Date  ICMJE October 2015
Estimated Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 20, 2015)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02584283 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 20, 2015)
  • 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
  • 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.
  • 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.
  • Graft (censored and uncensored for patient death) survival [ Time Frame: 7 days, 1, 3 , 6 months after transplantation ]
  • Patient survival [ Time Frame: 7 days, 1, 3 , 6 months after transplantation ]
  • 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
  • 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
  • Blood pressure [ Time Frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion ]
    mm Hg
  • Heart rate [ Time Frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion ]
    beats per minute
  • Vasopressor dosage [ Time Frame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion ]
    microgram/kg/min
  • 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
  • Postoperative complications [ Time Frame: 6 months ]
    According to the comprehensive complication index (CCI)
  • 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
  • Flow [ Time Frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion ]
    ml/min
  • Pressure [ Time Frame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion ]
    mm Hg
  • Resistance [ Time Frame: 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 [ Time Frame: 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 [ 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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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
  • (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 ]
  • (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
  • (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
  • (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
  • (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
  • (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
  • 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 ]
  • 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.
  • 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
  • Health related quality of life [ Time Frame: within 6 months before transplantation and 6 months after transplantation ]
    EQ6D questionnaire
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Liver Failure
  • End Stage Liver Disease
  • Biliary Tract Diseases
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Procedure: Dual hypothermic oxygenated perfusion
    • Device: Liver Assist®
    • Procedure: Perfusion fluid
    • Drug: Glutathione
  • 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.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 20, 2015)
156
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2019
Estimated Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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, Hepatitis B or C
  • Simultaneous transplantation of another organ
  • Patients with contra-indications for MRCP (i.e. pacemaker)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Robert J. Porte, MD PhD Prof 0031503619027 r.j.porte@umcg.nl
Contact: Rianne van Rijn, MD 0031652724616 r.van.rijn@umcg.nl
Listed Location Countries  ICMJE Belgium,   Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02584283
Other Study ID Numbers  ICMJE DHOPE-DCD Trial
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Robert J. Porte, University Medical Center Groningen
Study Sponsor  ICMJE Robert J. Porte
Collaborators  ICMJE
  • Erasmus Medical Center
  • Leiden University Medical Center
Investigators  ICMJE
Principal Investigator: Robert J. Porte, MD PhD Prof University Medical Center Groningen
PRS Account University Medical Center Groningen
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP