Investigation of the ischemia-reperfusion injury in patients who will undergo a liver transplantation after receiving a drug combination/multifactorial modulation
Conditions
Interventions
Trade Name: Circadin
Product Name: Circadin
Pharmaceutical Form: Prolonged-release tablet
Trade Name: Flolan
Sponsors
UZ Leuven
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Older than 18 years, -Patients undergoing liver transplantation in University Hospitals Leuven, Centre Hospitalier Universitaire de Liège and at other national and international centers. -Patient must have signed the patient informed consent, -All donor types: donation after brain death (DBD), donation after cardiac death (DCD), standard criteria donors (SCD) and extended criteria donors (ECD) defined according Paris consensus Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 90 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
Exclusion criteria: -Patients who refuse to participate in the study, - History of hypersensitivity to anti-thrombin III (Atenativ®), C1-inhibitor (Cetor®/Cinryze®), melatonin (Circadin®), epoprostenol (Flolan®), recombinant human EPO (Neorecormon®), infliximab (Remicade®), glutathione (Tationil®), tocopferol (vitamin e suspension 100 mg/mL®) will be excluded from the treatment group. - Conditions that prevent the use of the multifactorial modulation: - Administration of heparin at therapeutic dose pre-operatively: anti-thrombin III (Atenativ®), epoprostenol (Flolan®). - Congestive heart failure arising from severe left ventricular dysfunction: epoprostenol (Flolan®), infliximab (Remicade®). - History of seizures (not related to the underlying liver disease or to metabolic disturbances secondary to liver cirrhoris and to be distuinghuised from e.g. hepatic encephalopathy), poorly controlled arterial hypertension, myocardial infarction or stroke in the month preceding the liver transplantation, and history of pre-existing venous thromboembolic disease which is not related to liver cirrhosis and hypercoagulability (eg. partial, complete or previous vena porta thrombosis/ vena mesenterica thrombosis/ vena lienalis): recombinant human EPO (Neorecormon®). - Unstable angina pectoris: recombinant human EPO (Neorecormon®). - Severe untreated infections such as sepsis, abscesses and opportunistic infections: infliximab (Remicade®). - Use of Vitamin K antagonist anticoagulation preoperatively which can not be reversed, women taking oral contraceptives containing oestrogens: tocopferol (vitamin E suspension 100 mg/mL®). - Patients with previous treatment of infliximab (Remicade®), Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial, - Combined organ transplantation, - Re-transplantation, - Patients that are dialysis-dependent prior to LTx, - LTx from a living or a split organ donation - Administration of the multifactorial modulation technically non-feasible (i.e impossibility to place the second central catheter required for the separate and sequential injection of the different components of the multifactorial modulation).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate - the safety of the drug combination/multifactorial modulation - the effectiveness of the drug combination/multifactorial modulation in reducing the peak of aspartate amino transferase (AST) – a surrogate marker of ischemia-reperfusion injury (IRI) - after liver transplantation. ;Secondary Objective: not applicable;Primary end point(s): The primary endpoint is the log-transformed peak AST, where peak AST is defined as the highest value of serum AST within 72 hours following liver transplantation.;Timepoint(s) of evaluation of this end point: -day of transplantation (= baseline) -before hepatectomy -before reperfusion -30,60,120 minutes after reperfusion -6,12,24,48,72 hours after reperfusion | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Graft loss: Graft loss is defined as the need for retransplantation within one week post LTx due to a non-life-sustaining liver graft function (primary non function (PNF)) or later (other reason). -Recipient death -Early graft dysfunction as defined by Olthoff: the presence of one or more of the following postoperative laboratory analyses: bilirubin = 10mg/dL on day 7, international normalized ratio = 1.6 on day 7, and alanine aminotransferase (ALT) or AST > 2000 IU/L within the first 7 days. -Incidence of biliary strictures: a biliary stricture is defined as a narrowing within the biliary tree, radiologically evident [endoscopic retrograde cholangio-pancreatography (ERCP) and/or magnetic resonance cholangiopancreatography (MRCP)] to cause clinical symptoms or biochemical abnormalities requiring intervention (ERCP, percutanous transhepatic cholangiographic (PTC) drainage, surgery, retransplantation). Biliary strictures are categorized as anastomotic or non-anastomotic based on the cholangiographic appearance of the biliary tree as judged by a blinded radiologist. Non-anastomotic strictures are defined as any strictures, dilatation, or irregularity of the intra- or extrahepatic bile ducts of the liver graft at a site(s) other than that of the anastomosis. Intra-hepatic biliary strictures are classified in 4 groups: unilateral focal, confluence, bilateral multifocal and diffuse necrosis. Beside the routine 1 year post-transplant assessment of the biliary tree by MRCP, biliary strictures will be investigated in case of clinical or biochemical suspicion (based upon cholestasis). Other causes leading to cholestasis (e.g. hepatic artery thrombosis, bile leakage, rejection or cholangitis) will be excluded based on state-of-the-art radiological and histological examination as part of the routine standard treatment of care. These examinations include ultrasound Doppler, CT and CT angiogram, biopsy-proven rejection based on histology scored by 2 | — |
Countries
Belgium
Contacts
Public ContactDiethard Monbaliu
UZ Leuven
Outcome results
None listed