An interventional study of In-situ perfusion: aNRP and Ex-situ perfusion: DHOPE/DHOPE-COR-NMP in Liver Disease (Alcoholic or Not) and Transplantation, sponsored by Leiden University Medical Center. Recruiting at 3 sites in Netherlands. Open to participants aged 16 Years and older. Per ClinicalTrials.gov, last updated 2026-11-03.
Sponsored by Leiden University Medical Center · Not applicable, Interventional, and Treatment
The goal of this Randomized Controlled Trial is to learn what machine preservation method is most clinically effective for liver transplantation (LTx) after donation after circulatory death (DCD). The main questions it aims to answer are:
Researchers will compare preservation using in-situ abdominal normothermic regional perfusion (aNRP) to (dual) hypothermic oxygenated perfusion (DHOPE) or DHOPE followed by controlled oxygenated rewarming and normothermic machine perfusion (DHOPE-COR-NMP).
Nothing will change from clinical practice for the liver recipients.
RELEVANCE Around 15% of waiting-list patients for liver transplantation are removed prematurely due to death or clinical deterioration. To reduce donor liver shortage, lower-quality livers are increasingly used, including those from donation after circulatory death (DCD), though these carry a higher risk of complications. Several machine perfusion techniques have been developed to recondition and/or assess donor livers: 'in situ' abdominal Normothermic Regional Perfusion (aNRP), and 'ex-situ' Dual Hypothermic Oxygenated Perfusion (DHOPE), in some cases followed by Controlled Oxygenated Rewarming (COR) and Normothermic Machine perfusion (NMP). All these techniques are reimbursed as proven effective treatment in the Netherlands. It remains unclear which strategy is most effective and cost-efficient for DCD livers. A direct comparison is needed to answer this question and decide on a future standard of care.
RESEARCH QUESTION Which machine perfusion technique is most clinically effective and cost-effective for liver transplantation after DCD?
HYPOTHESIS In situ preservation using aNRP reduces the one year incidence of total biliary complications when compared to ex situ preservation with DHOPE (±COR-NMP), with potential cost advantages.
INTERVENTION In situ perfusion (aNRP), restores oxygenated circulation to abdominal organs shortly after donor cardiac arrest to protect organs and allow functional assessment. In standard risk (SCD)-DCD livers, perfusion is performed for one hour without viability assessment. If (re)classified as high risk (extended criteria or ECD)-DCD liver, perfusion continues for two hours, including viability assessment.
COMPARISON The current standard ex-situ perfusion techniques in DCD liver transplantation: DHOPE for standard-risk SCD-DCD livers; or DHOPE-COR-NMP for ECD-DCD livers.
FOLLOW-UP TIME 60 month inclusion time, 12 month follow-up post-transplantation
STUDY DESIGN Multicenter 1:1 randomized controlled trial. DCD livers will be randomized (Castor EDC) after stratification for type (SCD-DCD or ECD-DCD) and transplantation center. Donor characteristics will be obtained from the Eurotransplant Registry, and perfusion parameters recorded prospectively. Recipient data will be extracted from electronic medical records for mandatory Netherlands Organ Transplant Registry (NOTR) registration.
SAMPLE SIZE \& DATA ANALYSIS SCD-DCD 156 liver transplantations per group, total 312. ECD-DCD 102 liver transplantations per group, total 204. Overall: 516 liver transplantations.
Estimated randomizations: 752 total, approximately 236 procedures/randomisations do not result in transplantation due to long agonal phase and viability assessment.
824 studies on the registry are indexed under Liver Diseases; 152 are open to participants now.
This study's planned enrollment of 752 is above the median of 52 across 521 interventional studies indexed under Liver Diseases.
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Exclusion Criteria:
This arm contains of 2 pre-defined strata: SCD-DCD livers: receiving DHOPE, ECD-DCD livers: receiving DHOPE-COR-NMP. Both treatments are standard of care.
Procedure: Ex-situ perfusion: DHOPE/DHOPE-COR-NMP
This arm contains of 2 pre-defined strata: SCD-DCD livers: receiving 1 hour of aNRP, ECD-DCD livers: receiving 2 hours of aNRP. Both treatments are standard of care.
Procedure: In-situ perfusion: aNRP
This arm contains of 2 pre-defined strata: SCD-DCD livers: receiving 1 hour of aNRP, ECD-DCD livers: receiving 2 hours of aNRP. Both treatments are standard of care.
This arm contains of 2 pre-defined strata: SCD-DCD livers: receiving DHOPE, ECD-DCD livers: receiving DHOPE-COR-NMP. Both treatments are standard of care.
one-year cumulative incidence of biliary complications
Death censored incidence of biliary complications including biliary anastomotic strictures, post-transplant cholangiopathy and biliary leakages, all that necessitate intervention
Time frame: 1 year
cost-effectiveness
QALYs derived from EQ-5D-5L questionnaire measured at six time points: waitlist registration, and at six weeks, three, six, twelve and twenty-four months post-transplantation. If aNRP is estimated to lead to higher costs as well as better health outcomes or to lower costs and worse health outcomes, an incremental cost-effectiveness ratio (ICER) will be calculated (costs per QALY gained or savings per QALY lost). If not, one treatment will be considered dominant. As aNRP perfuses multiple organs at once, the overall costs per procedure and subsequent transplantations will be researched.
Time frame: 5 year
Post transplant cholangiopathy rate
Narrowing or irregularity of intra- or extra-hepatic donor bile duct excluding the biliary anastomosis leading to clinical symptoms or laboratory derangements in the absence of hepatic artery thrombosis for which an invasive intervention is required.
Time frame: 1 year
patient QOL
Health-Related Quality of Life via PROMIS questionnaire: Patient-Reported Outcomes Measurement Information System, that assesses seven core health domains using 4-item short form items plus one pain intensity item (scale 0-10, with 10 worse outcome).
Time frame: 2 year
Patient mortality
Recipient death
Time frame: 1 year
Graft loss
Failure of the liver allograft requiring either re-transplantation or leading to recipient mortality.
Time frame: 1 year
post-transplant overall complications
Also including vascular complications (hepatic artery and portal vein thrombosis) And complications graded as Clavien Dindo =\> 3a, and the comprehensive complication index
Time frame: 1 year
duration of hospital and ICU stay
In days
Time frame: 1 year
Environmental Demand
Environmental Demand: Measured in global hectares (gha). Converts all physical inputs (Greenhouse Gas Emissions: Measured in kg CO₂e, Electricity: Measured in kWh an Consumables \& Waste: Measured in kg of waste and liters (L) of fluids) into the total biophysical land area required to support each distinct protocol.
Time frame: 1 year
Liver utilization rate
How many livers are transplanted and still functioning from organ offer to 1 year post transplantation. It takes in account the acceptance rate, discard rate, transplant rate and 1-year survival.
Time frame: 1 year
Postoperative intra-abdominal bleeding
Clinically significant bleeding event requiring percutaneous or surgical re-intervention
Time frame: During index in-hospital stay, on average 9 days
Presence of post reperfusion syndrome
A drop in mean arterial pression ≥30% from the baseline for at least 1 min and within 5 min from reperfusion
Time frame: During transplantation
Need for renal replacement therapy
Any extracorporeal therapy to supplement or replace renal function that was not present before transplant
Time frame: During index in-hospital stay, on average 9 days
Intervention rates
e.g. MRCP, ERCP and percutaneous transhepatic cholangiography drainage
Time frame: 1 year
Reoperation rate
Number of reoperations
Time frame: 1 year
Early Allograft Failure Simplified Estimation Score
EASE = -0.602 + 0.044\*(MELD at transplant) + 0.065\*(number of PACKED RED BLOOD CELL transfused units during surgery) + 2.567 (if arterial or portal thrombosis during days 1-10) + 0.000534\*(AUC ln AST in POD1,2,3,7,10)2 - 0.093\*(AUC ln PLT in POD1,3,7,10) - 7.766\*(slope ln PLT in POD1,3,7,10) + 0.795\*(slope ln billirubin in POD1,3,7,10) - 0.402 (if center volume ≥70 cases per year). Five EASE risk groups for graft and patient survival were defined as follows: (1) risk group 1: EASE score \< -3.43; (2) risk group 2: -3.43 ≤ EASE score ≤ -1.26; (3) risk group 3: -1.25 ≤ EASE score ≤ -0.75; (4) risk group 4: -0.74 ≤ EASE score ≤ -0.01 (5) risk group 5: 0 ≤ EASE score ≤ 5. Risk group 5 is the worse outcome.
Time frame: 10 days post operative
Retransplantation rate
Failure of the liver allograft requiring explant and replacement with an alternative liver graft
Time frame: 1 year
Primary non function rate
Graft loss, re-transplantation, or patient death within 14 days of initial transplantation not secondary to hepatic artery thrombosis, biliary complication, recurrent disease or acute rejection.
Time frame: 14 days
Anastomotic stricture
Localized narrowing of the biliary anastomosis between the donor and recipient bile ducts for which an invasive intervention is required.
Time frame: 1 year
Bile leak
Extra-luminal escape of biliary contents that requires invasive intervention (percutaneous or surgical)
Time frame: 1 year
Early allograft dysfunction
Enzymatic changes related to slow-resolving recipient liver disease that resolves without treatment should not be graded as a complication. Enzymatic changes related to an initially impaired graft function leading to more frequent observation (ie, laboratory tests, repeat ultrasound). Officially diagnosed if a patient meets at least one of the following lab conditions: AST or ALT \> 2000 IU/L within the first 7 postoperative days, total bilirubin \>= 10 mg/dL on postoperative day 7. International normalized ratio (INR) +. 1.6 on postoperative day 7.
Time frame: Postoperative day 7
Death censored graft survival
the probability that a transplanted organ is still functioning exactly one year after the procedure, excluding patients who died with a working organ from the failure count
Time frame: 1 year
Overall graft survival
the probability that a transplanted organ is still functioning exactly one year after the procedure
Time frame: 1 year
Patient survival
all-cause mortality within 365 days post-transplantation
Time frame: 1 year
Accumulated team member working hours
For assessing personnel sustainability. Team members include retrieving surgeons, organ perfusionists, organ donation coordinators, organ transplantation coordinators, transplant surgeons, scrub nurses during retrieval and transplantation, anesthesiologists, anesthetics nurse, drivers.
Time frame: 1 year
Readmission rate
Number of readmissions
Time frame: 1 year
Creatinine values
before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in µmol/L.
Time frame: 5 years
Sodium values
before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in mmol/L.
Time frame: 5 years
Alkaline Phosphatase values
In short: ALP. Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in U/L.
Time frame: 5 years
Alanine Aminotransferase values
In short: ALT. Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in U/L.
Time frame: 5 years
gamma-Glutamyl Transferase values
In short: GGT. Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in U/L.
Time frame: 5 years
Bilirubin values
Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in µmol/L.
Time frame: 5 years
Aspartate Aminotransferase values
In short: AST. Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in U/L.
Time frame: 5 years
International Normalized Ratio values
In short: INR. Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years.
Time frame: 5 years
Thrombocytes values
Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured /L.
Time frame: 5 years
Urea values
Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in mmol/L.
Time frame: 5 years
eGFR values
Measured before LTx, post-LTx days 1-7 and 10, 6 months, 1, 3 and 5 years. Measured in mL/min/1.73m²
Time frame: 5 years
Utilized organs per donor
Number of organs transplanted per donor
Time frame: Peri-operative
Plan to share: No — IPD will not be shared. Anonimization of data needs to be addressed to provide sufficient patient and donor privacy according to national law.
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