Clinical trial NCT02251041: Combined Drug Approach to Prevent Ischemia-reperfusion Injury During Transplantation of Livers (CAPITL)
Official title: Combined Drug Approach to Prevent Ischemia-reperfusion Injury During Transplantation of Livers (CAPITL): a First-in-men Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Reperfusion Injury
Keywords: Liver
Transplantation
Ischemia-reperfusion
Effectiveness
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2014-09-26
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Peak Aspartate Aminotransferase Within First 72h Post Transplant
timeFrame: within 72 hours following liver transplantation
Secondary outcomes:
measure: Graft Loss
timeFrame: 3 and 12 months after liver transplantation
measure: Recipient Death
timeFrame: 3 and 12 months after liver transplantation
measure: Early Graft Dysfunction
timeFrame: within first 7 days
measure: Number of Participants Developing Biliary Strictures
timeFrame: within 12 months post transplantation
measure: Ischemia Reperfusion Injury Score
timeFrame: One hour post reperfusion
measure: Graft Rejection
timeFrame: till 1 year after transplantation
measure: Patients With at Least 1 Severe Surgical Complications
timeFrame: within 1 year after liver transplantation
measure: Non-anastomotic Biliary Stricture
timeFrame: 1 year
measure: Acute Kidney Injury Score
timeFrame: 48h
measure: Post-Reperfusion Syndrome
timeFrame: first 5 minutes following graft reperfusion
Other outcomes:
measure: Intensive Care Unit Length of Stay (Recipient)
timeFrame: During hospital stay for liver transplantation
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven
Study officials:
affiliation: Abdominal transplant surgery - transplant coordination, Abdominal transplant surgery lab (microbiology & immunology Dpt)
name: Diethard Monbaliu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.