Combined Drug Approach to Prevent Ischemia-reperfusion Injury During Transplantation of Livers (CAPITL)

Phase 2

Completed

Conditions: Reperfusion Injury

Interventions: Drug: Antithrombin-III
Drug: Sodium chloride solution
Drug: Infliximab
Drug: Apotransferrin
Drug: Human recombinant erythropoietin
Drug: C1-Inhibitor
Drug: Glutathione
Drug: Alfa-tocopherol
Drug: Melatonin
Drug: Epoprostenol

Registration Number: NCT02251041

Lead Sponsor: Universitaire Ziekenhuizen KU Leuven

Brief Summary: The purpose of this study is to establish the effectiveness of the combined drug approach (anti-thrombin III, infliximab, apotransferrin, human recombinant erythropoietin beta, C1-inhibitor, glutathione, alfa-tocopherol, melatonin and epoprostenol)aimed to reduce ischemia-reperfusion injury during liver transplantation in eligible recipients.

Detailed Description: This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020.

Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase.

The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 143

Inclusion Criteria

Patients suffering from irreversible liver failure eligible for liver transplantation according to Eurotransplant guidelines.
Patients > 18 years of age at time of listing on Eurotransplant waiting list for liver transplantation in University Hospitals Leuven, Belgium.

Exclusion Criteria

Patients who refuse to participate in the study.
History of hypersensitivity to one/several component(s) of the combined drug approach.
Conditions that prevent the use of the combined drug approach:
- Administration of heparin at therapeutic dose pre-operatively,
- Congestive heart failure,
- History of seizure, poorly controlled arterial hypertension, myocardial infarction or stroke in the month preceding the liver transplantation, venous thromboembolic disease,
- Unstable angina pectoris,
- Sepsis, abcesses or opportunistic infections,
- History of infliximab treatment,
- Use of vitamin K antagonist anticoagulation.
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 the liver transplantation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
cases	Apotransferrin	the group receives a combination of drugs
cases	Alfa-tocopherol	the group receives a combination of drugs
cases	C1-Inhibitor	the group receives a combination of drugs
cases	Antithrombin-III	the group receives a combination of drugs
cases	Infliximab	the group receives a combination of drugs
cases	Glutathione	the group receives a combination of drugs
cases	Melatonin	the group receives a combination of drugs
cases	Epoprostenol	the group receives a combination of drugs
controls	Sodium chloride solution	the group do not receive a combination of drugs, but a placebo (sodium chloride solution)
cases	Human recombinant erythropoietin	the group receives a combination of drugs

Primary Outcome Measures

Name	Time	Method
Peak Aspartate Aminotransferase Within First 72h Post Transplant	within 72 hours following liver transplantation	peak AST is defined as the highest value of serum AST within 72 hours following liver transplantation

Secondary Outcome Measures

Name	Time	Method
Early Graft Dysfunction	within first 7 days	early graft dysfunction as defined by Olthoff
Ischemia Reperfusion Injury Score	One hour post reperfusion	Ischemia Reperfusion Injury score 1h post reperfusion by using the Suzuki score and Monbaliu et al. The score ranges from 0 (no injury) to 4 (severe injury).
Acute Kidney Injury Score	48h	An acute kidney injury score of 1 indicates risk; 2, injury; and 3, failure. According to RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) Minimum score is 0 meaning there is no injury, maximum score is 3 meaning failure of the organ.
Non-anastomotic Biliary Stricture	1 year	Non-anastomotic biliary stricture at 1 year
Graft Loss	3 and 12 months after liver transplantation	graft loss at 3 and 12 months after liver transplantation
Graft Rejection	till 1 year after transplantation	a liver biopsy will be taken after transplantation and in case of clinical suspicion of acute rejection
Recipient Death	3 and 12 months after liver transplantation	recipient death at 3 and 12 months after liver transplantation
Number of Participants Developing Biliary Strictures	within 12 months post transplantation	Biliary strictures are the narrowing of the intrahepatic or extrahepatic biliary ductal system. Here we report the number of participants developing biliary strictures within 12 months post transplantation by MRCP (magnetic resonance cholangiopancreatography)
Patients With at Least 1 Severe Surgical Complications	within 1 year after liver transplantation	The ranking of surgical complications will be done by using Clavien-Dindo classification Grade I Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics, analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are opened at the bedside Grade II Complications requiring drug treatments other than those allowed for Grade I complications; this includes blood transfusion and total parenteral nutrition (TPN) Grade III Complications requiring surgical, endoscopic or radiological intervention Grade IV Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient ischaemic attacks (TIAs) Grade V Death of the patient A severe surgical complication is defined as Grade III or higher.
Post-Reperfusion Syndrome	first 5 minutes following graft reperfusion	Post-reperfusion syndrome defined as a 30% decrease of mean systemic blood pressure for more than 1 minute during the first 5 minutes following graft reperfusion