Evaluation of the Effect of Gabexate Mesilate in the Hepatocyte Protection After Liver Resection

Liver resection have been a primary treatment option for lesions found in the liver. With improvements in surgical technique and perioperative patient management, morbidity and mortality related to liver resection have been greatly reduced. However, many patients with hepatocellular carcinoma have underlying liver disease. Severity of underlying liver disease plays an important role in decision making of resection extent. Therefore, liver failure and decreased liver function following liver resection still remains to be an critical issue.

Postresection liver failure is generally defined by serum total bilirubin greater than 3mg/dL and prothrombin time of less than 50% of normal (INR >1.7). Pathophysiology of postresection liver failure is not yet well known. However, sepsis after liver resection, small-for-size syndrome (SFSS), and ischemia/reperfusion injury are known to have important roles in persistant liver injury after resection.

After a liver resection, kupffer cells are drastically decreased and innate immunity of the patient is also damaged. This process causes the patient to be vulnerable to infection. In addition, with continuous endotoxin secretion, dysfunction in kupffer cells are triggered and liver regeneration is affected.

Complex mechanisms leading to dysfunctional kupffer cells and apoptosis and necrosis of hepatocytes are mediated by neutrophils, complement, reactive oxygen species, and acute inflammatory cytokines.

Recent studies have reported on many promising effects of the synthetic protease inhibitor, such as Gabexate mesilate. These include antioxidant effect, inhibition of acute inflammatory cytokine reaction, and anticoagulatory property. Based on these effects, synthetic protease inhibitor have gained attention in the role of hepatocyte protection after liver resection.

Currently, there is a report on the hepatocyte protective effects of Gabexate Mesilate on ischemia/reperfusion injury caused by the Pringle maneuver. However, with the advances in surgical technique and equipment, many surgeons now perform liver resection without Pringle maneuver. Therefore, this study was designed to determine effects of Gabexate Mesilate in the liver resection performed without Pringle maneuver.

Study Overview

• Status: Terminated
• Conditions: Liver Disease
• Intervention / Treatment: Drug: hepatectomy with dextrose water; Drug: Preoperative Gabexate Mesilate group; Drug: Intraoperative Gabexate Mesilate group

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All liver tumors that require resection of more than two segments of the liver.
• Age ≥20 and ≤80
• General performance status: the Karnofsky score> 70% or ECOG 0-1

Exclusion Criteria:

• Hepatic duct reconstruction was performed
• ASA (American society of anesthesiologists' physical status classification) score: ≥3
• Patients with drug or alcohol addiction
• Patients showing low compliance
• Patients who not want to involve the clinical trial
• Patients who are unable to read or understand the informed consent, sign a consent form (eg, mental retardation, blindness, illiteracy, foreign, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo group; hepatectomy without Gabexate Mesilate	Drug: hepatectomy with dextrose water; Gabexate Mesilate is not administered. As placebo, 500cc of 5% dextrose water is administered at 40cc/hr for 12 hours
EXPERIMENTAL: Preoperative Gabexate Mesilate group; Gabexate Mesilate administered from the preoperative day	Drug: Preoperative Gabexate Mesilate group; Gabexate Mesilate is administered from the preoperative day and continued for 5 days. 300mg of Gabexate Mesilate is mixed with 500cc of 5% dextrose water and administered at 40cc/hr for 12 hours each day.
EXPERIMENTAL: Intraoperative Gabexate Mesilate group; Gabexate Mesilate administered from the operative day	Drug: Intraoperative Gabexate Mesilate group; Gabexate Mesilate is administered from the operative day and continued for 5 days. 300mg of Gabexate Mesilate is mixed with 500cc of 5% dextrose water and administered at 40cc/hr for 12 hours each day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Postoperative complications	Within the first 30 days after surgery

Secondary Outcome Measures

Outcome Measure	Time Frame
Liver function recovery time	4 weeks
length of hospitalization	4 weeks

Collaborators and Investigators

• Sponsor: Yonsei University

Publications and helpful links

General Publications

• Kim YI, Fujita S, Hwang YJ, Chun JM, Song KE, Chun BY. Successful intermittent application of the Pringle maneuver for 30 minutes during human hepatectomy: a clinical randomized study with use of a protease inhibitor. Hepatogastroenterology. 2007 Oct-Nov;54(79):2055-60.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 24, 2012
• Primary Completion (ACTUAL): February 25, 2017
• Study Completion (ACTUAL): February 25, 2017

Study Registration Dates

• First Submitted: February 1, 2016
• First Submitted That Met QC Criteria: March 11, 2016
• First Posted (ESTIMATE): March 16, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 18, 2018
• Last Update Submitted That Met QC Criteria: July 15, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Hepatectomy; Postoperative Complications; Synthetic Protease Inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; Gabexate
• Other Study ID Numbers: 4-2011-0936

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO