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

• Study Type: Interventional
• Enrollment (Actual): 72
• 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
• Genders Eligible for Study: All

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
• 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: controles; 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
log-transformed peak AST	log-transformed peak AST, where 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
Incidence of biliary strictures	Incidence of biliary strictures within 12 months post transplantation by MRCP (magentic resonance cholangiopancreatography)	within 12 months post transplantation
IRI score	IRI score during transplantation, 1 week and 1 year after liver transplantation by using the Suzuki score and Monbaliu et al.	during transplantation, 1 week and 1 year after
Graft rejecton	a liver biopsy will be taken after transplantation and in cas of clinical suspicion of acute rejection	till 1 year after transplantation
Surgical complications	the ranking of surgical complications will be done by using Clavien-Dindo classification	within 30 days after liver transplantation

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven

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 (ESTIMATE): September 26, 2014

Study Record Updates

• Last Update Posted (ACTUAL): August 9, 2019
• Last Update Submitted That Met QC Criteria: August 8, 2019
• 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; 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; 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