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

Combined Drug Approach to Prevent Ischemia-reperfusion Injury During Transplantation of Livers (CAPITL): a First-in-men Study

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.

Study Overview

• Status: Completed
• Conditions: Reperfusion Injury
• Intervention / Treatment: Drug: Melatonin; Drug: Infliximab; Drug: Glutathione; Drug: Epoprostenol; Drug: Human recombinant erythropoietin; Drug: Antithrombin-III; Drug: Apotransferrin; Drug: C1-Inhibitor; Drug: Alfa-tocopherol; Drug: Sodium chloride solution

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.

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • University Hospitals Leuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Patients who refuse to participate in the study.
2. History of hypersensitivity to one/several component(s) of the combined drug approach.

3. 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.
4. Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial.
5. Combined organ transplantation.
6. Re-transplantation.
7. Patients that are dialysis-dependent prior to the liver transplantation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: cases; the group receives a combination of drugs	Drug: Melatonin; Drug: Infliximab; Drug: Glutathione; Drug: Epoprostenol; Drug: Human recombinant erythropoietin; Drug: Antithrombin-III; Drug: Apotransferrin; Drug: C1-Inhibitor; Drug: Alfa-tocopherol
Placebo Comparator: controls; the group do not receive a combination of drugs, but a placebo (sodium chloride solution)	Drug: Sodium chloride solution

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft Loss	graft loss at 3 and 12 months after liver transplantation	3 and 12 months after liver transplantation
Recipient Death	recipient death at 3 and 12 months after liver transplantation	3 and 12 months after liver transplantation
Early Graft Dysfunction	early graft dysfunction as defined by Olthoff	within first 7 days
Number of Participants Developing Biliary Strictures	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)	within 12 months post transplantation
Ischemia Reperfusion Injury Score	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).	One hour post reperfusion
Graft Rejection	a liver biopsy will be taken after transplantation and in case of clinical suspicion of acute rejection	till 1 year after transplantation
Patients With at Least 1 Severe Surgical Complications	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.	within 1 year after liver transplantation
Non-anastomotic Biliary Stricture	Non-anastomotic biliary stricture at 1 year	1 year
Acute Kidney Injury Score	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.	48h
Post-Reperfusion Syndrome	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	first 5 minutes following graft reperfusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensive Care Unit Length of Stay (Recipient)	Intensive Care Unit stay immediately after liver transplantation (not after rehospitalization)	During hospital stay for liver transplantation

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Diethard Monbaliu, MD, PhD, Abdominal transplant surgery - transplant coordination, Abdominal transplant surgery lab (microbiology & immunology Dpt)

Publications and helpful links

General Publications

• Monbaliu D, Vekemans K, Hoekstra H, Vaahtera L, Libbrecht L, Derveaux K, Parkkinen J, Liu Q, Heedfeld V, Wylin T, Deckx H, Zeegers M, Balligand E, Buurman W, van Pelt J, Porte RJ, Pirenne J. Multifactorial biological modulation of warm ischemia reperfusion injury in liver transplantation from non-heart-beating donors eliminates primary nonfunction and reduces bile salt toxicity. Ann Surg. 2009 Nov;250(5):808-17. doi: 10.1097/SLA.0b013e3181bdd787.
• Vekemans K, Monbaliu D, Balligand E, Heedfeld V, Jochmans I, Pirenne J, van Pelt J. Improving the function of liver grafts exposed to warm ischemia by the Leuven drug protocol: exploring the molecular basis by microarray. Liver Transpl. 2012 Feb;18(2):206-18. doi: 10.1002/lt.22446.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): February 1, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: September 24, 2014
• First Submitted That Met QC Criteria: September 25, 2014
• First Posted (Estimated): September 26, 2014

Study Record Updates

• Last Update Posted (Actual): August 23, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Transplantation; Effectiveness; Liver; Ischemia-reperfusion
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Ischemia; Wounds and Injuries; Reperfusion Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Platelet Aggregation Inhibitors; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Protease Inhibitors; Protective Agents; Dermatologic Agents; Micronutrients; Vitamins; Serine Proteinase Inhibitors; Anticoagulants; Antioxidants; Hematinics; Tumor Necrosis Factor Inhibitors; Complement Inactivating Agents; Melatonin; Epoetin Alfa; Epoprostenol; Vitamin E; Tocopherols; alpha-Tocopherol; Infliximab; Complement C1 Inhibitor Protein; Antithrombins; Antithrombin III; Tezosentan
• Other Study ID Numbers: CAPITL RCT