Effect of Candesartan in Alcoholic Liver Fibrosis

Alcoholic Liver Disease Clinical Trial

Official title:

Beneficial Effect of Angiotensin-blocking Agent Candesartan on Alcoholic Liver Fibrosis: A Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00990639
• Other study ID #: YWhep091
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 6, 2009
• Last updated: October 6, 2009
• Start date: September 2005
• Est. completion date: March 2009

Study information

• Verified date: October 2009
• Source: Yonsei University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Institutional Review BoardKorea: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Background:

Alcohol is one of principal causes of hepatic fibrosis. Although the most effective treatment for alcoholic hepatic fibrosis is abstinence of alcohol consumption, additive treatment to reduce the accumulation of scar tissue can accelerate the improvement of hepatic fibrosis in alcoholic liver disease. The renin-angiotensin system can be an attractive antifibrotic target in liver. Several lines of evidence indicate that overproduction of angiotensin II(ANG II) in chronic liver injury stimulates the activation of hepatic stellate cells(HSCs) attributed to fibrogenesis. Additionally, the antifibrotic effect of ANG II blocking agent has been shown in various animal models and hepatitis C patients. Hence, drugs that inhibit the renin-angiotensin system have promise in ameliorating hepatic fibrosis in chronic liver injury. However, no study has been conducted in patients with alcoholic liver disease to evaluate the effect ANG II type I receptor blocking agent on hepatic fibrosis.

Aim:

This study aimed to investigate the safety and the efficacy of chronic administration of candesartan to hepatic fibrosis patients with alcoholic liver disease.

Methods

1) Patients with liver fibrosis(F2) were randomized to receive either the angiotensin receptor blocker(ARB), candesartan(8 mg/day) with ursodeoxycholic acid(UDCA)(600 mg/day)(n = 42), or UDCA alone(n = 43) as control for 6 months. 2)All enrolled patients underwent liver biopsies twice for measurement of fibrosis score, area of fibrosis and alpha-smooth muscle actin(SMA) positive and hydroxyproline. 3) Transforming growth factor-beta1(TGF-beta1), collagen-1, angiotensin II type I receptor(AT1-R), tissue inhibitor of metalloproteinase-1(TIMP-1), Rac1 and p22phox which represent oxidant stress were also measured by real-time RT-PCR before and after 6 months of therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: March 2009
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Clinical diagnosis of alcoholic liver disease

• METAVIR fibrosis score = 2 in liver biopsy

• Alcohol intake has stop during at least 6 months until study enrollment

Exclusion Criteria:

• Hepatocellular carcinoma or other malignancy

• Clinically decompensated cirrhosis (Total bilirubin = 5mg/dL or variceal hemorrhage or ascites development or hepatic encephalopathy developement)

• Chronic liver disease related with other causes except alcohol

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alcoholic Liver Disease
• Liver Diseases
• Liver Diseases, Alcoholic

Intervention

Drug:
• candesartan for hepatic fibrosis
Candesartan group(42 patients): oral candesartan at a daily dose of 8 mgin addition to ursodeoxycholic acid (UDCA, 600 mg/day) for 6 months. UDCA group(43 patients): oral ursodeoxycholic acid (UDCA, 600 mg/day) only for 6 months

Locations

Country	Name	City	State
Korea, Republic of	Yonsei University Wonju College of Medicine Wonju Christian Hospital	Wonju	Kangwon-do

Sponsors (1)

Lead Sponsor	Collaborator
Yonsei University

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (4)

Corey KE, Shah N, Misdraji J, Abu Dayyeh BK, Zheng H, Bhan AK, Chung RT. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int. 2009 May;29(5):748-53. doi: 10.1111/j.1478-3231.2009.01973.x. Epub 2009 Feb 9. — View Citation

Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, Brunello F, Alessandria C, Bonardi R, Saracco G, Rizzetto M, Marzano A. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol. 2007 Jun;46(6):1026-33. Epub 2007 Feb 9. — View Citation

Rimola A, Londoño MC, Guevara G, Bruguera M, Navasa M, Forns X, García-Retortillo M, García-Valdecasas JC, Rodes J. Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation. 2004 Sep 15;78(5):686-91. — View Citation

Terui Y, Saito T, Watanabe H, Togashi H, Kawata S, Kamada Y, Sakuta S. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology. 2002 Oct;36(4 Pt 1):1022. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improvement of histologic grade of hepatic fibrosis		6 month later	Yes
Secondary	estimation of safety of candesartan in hepatic fibrosis		6 month later	Yes