Clinical trial NCT02584283: Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Failure
End Stage Liver Disease
Biliary Tract Diseases
Keywords: Liver Transplantation
Donation after Circulatory Death
Machine Perfusion
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Leiden University Medical Center
name: Universitaire Ziekenhuizen KU Leuven
name: University Hospital, Ghent
name: King's College Hospital NHS Trust
First posted: 2015-10-22
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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).


Eligibility criteria: 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)

Primary outcomes:
measure: The incidence of symptomatic non-anastomotic biliary strictures (NAS)
timeFrame: 6 months
Secondary outcomes:
measure: Asymptomatic NAS
timeFrame: 6 months
measure: The severity of NAS
timeFrame: 6 months
measure: The location of NAS
timeFrame: 6 months
measure: Graft (censored and uncensored for patient death) survival
timeFrame: 7 days, 1, 3 , 6, and 12 months after transplantation
measure: Patient survival
timeFrame: 7 days, 1, 3 , 6, and 12 months after transplantation
measure: Primary non-function
timeFrame: 7 days
measure: Initial poor function
timeFrame: 7 days
measure: Biochemical analysis of graft function and ischemia-reperfusion injury
timeFrame: Postoperative day 0 - 7 and 1, 3, 6 months
measure: Blood pressure
timeFrame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
measure: Heart rate
timeFrame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
measure: Vasopressor dosage
timeFrame: 5 min before reperfusion, at reperfusion and after 10 and 20 minutes of reperfusion
measure: Length of stay
timeFrame: 6 months
measure: Postoperative complications
timeFrame: 6 months
measure: Renal function
timeFrame: day 7, and 1, 3, 6 months
measure: Flow
timeFrame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
measure: Pressure
timeFrame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
measure: Resistance
timeFrame: At 0, 15, 30, 45, 60, 75, 90, 105, 120 minutes after start of perfusion
measure: (In selected centers) value of perfusate's pH
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's sodium
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's potassium
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's bicarbonate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's lactate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's alanine transaminase (ALT)
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's aspartate transaminase (AST)
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's alkaline phosphatase (AlkP)
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's gamma glutamyltransferase (γGT)
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's urea
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's total bilirubin
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's thrombomodulin
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's high mobility group box-1 (HMBG) protein
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) value of perfusate's cytochrome C
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) level of miRNA CDmiR-30e in perfusate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) level of miRNA CDmiR-222 in perfusate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) level of miRNA CDmiR-296 in perfusate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) level of miRNA HDmiR-122 in perfusate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: (In selected centers) level of miRNA HDmiR-148a in perfusate
timeFrame: At 5 minutes before and at 0.5 hour, 1 hour, 1.5 hours and 2 hours after start of perfusion
measure: Histopathological status liver and bile ducts (in selected centers)
timeFrame: Within 0 to 30 minutes before perfusion, at 2 hours of perfusion, and at 1 hour after reperfusion
measure: New onset diabetes after transplantation
timeFrame: 90 days
measure: Costs of treatment (in selected centers)
timeFrame: within 6 months after transplantation, including transplant operation
measure: Health related quality of life
timeFrame: within 6 months before transplantation and 6 months after transplantation
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: Ghent University Hospital
state: De Pintelaan 185
city: Leuven
country: Belgium
facility: University Hospitals Leuven
state: Herestraat 49
city: Leiden
country: Netherlands
facility: Leiden Universtiy Medical Center
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: London
country: United Kingdom
facility: King's College Hospital NHS Trust
Study officials:
affiliation: University Medical Center Groningen
name: Robert J. Porte, MD PhD Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Rijn R, Schurink IJ, de Vries Y, van den Berg AP, Cortes Cerisuelo M, Darwish Murad S, Erdmann JI, Gilbo N, de Haas RJ, Heaton N, van Hoek B, Huurman VAL, Jochmans I, van Leeuwen OB, de Meijer VE, Monbaliu D, Polak WG, Slangen JJG, Troisi RI, Vanlander A, de Jonge J, Porte RJ; DHOPE-DCD Trial Investigators. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. N Engl J Med. 2021 Apr 15;384(15):1391-1401. doi: 10.1056/NEJMoa2031532. Epub 2021 Feb 24.
citation: de Vries Y, Berendsen TA, Fujiyoshi M, van den Berg AP, Blokzijl H, de Boer MT, van der Heide F, de Kleine RHJ, van Leeuwen OB, Matton APM, Werner MJM, Lisman T, de Meijer VE, Porte R. Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJ Open. 2019 Aug 15;9(8):e028596. doi: 10.1136/bmjopen-2018-028596.
citation: van Rijn R, van den Berg AP, Erdmann JI, Heaton N, van Hoek B, de Jonge J, Leuvenink HGD, Mahesh SVK, Mertens S, Monbaliu D, Muiesan P, Perera MTPR, Polak WG, Rogiers X, Troisi RI, de Vries Y, Porte RJ. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol. 2019 Mar 12;19(1):40. doi: 10.1186/s12876-019-0956-6.