Effect of Candesartan in Alcoholic Liver Fibrosis - Full Text View

Purpose

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.

Condition	Intervention	Phase
Alcoholic Liver Disease	Drug: candesartan for hepatic fibrosis	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Beneficial Effect of Angiotensin-blocking Agent Candesartan on Alcoholic Liver Fibrosis: A Randomized Controlled Trial

Resource links provided by NLM:

Genetics Home Reference related topics: North American Indian childhood cirrhosis

MedlinePlus related topics: Liver Diseases

Drug Information available for: Ursodiol Candesartan Candesartan cilexetil

U.S. FDA Resources

Further study details as provided by Yonsei University:

Primary Outcome Measures:

Improvement of histologic grade of hepatic fibrosis [ Time Frame: 6 month later ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

estimation of safety of candesartan in hepatic fibrosis [ Time Frame: 6 month later ] [ Designated as safety issue: Yes ]

Enrollment:	85
Study Start Date:	September 2005
Study Completion Date:	March 2009
Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: candesartan+UDCA group oral candesartan(8 mg/day) in addition to ursodeoxycholic acid (UDCA, 600 mg/day) for 6 months	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 Other Name: atacand for hepatic fibrosis
Placebo Comparator: UDCA group ursodeoxycholic acid(UDCA,600 mg/day)only for 6 months	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 Other Name: atacand for hepatic fibrosis

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00990639

Locations

Korea, Republic of
Yonsei University Wonju College of Medicine Wonju Christian Hospital
Wonju, Kangwon-do, Korea, Republic of, 220-701

Sponsors and Collaborators

Yonsei University

Investigators

Principal Investigator:

Soon Koo Baik, Professor

Yonsei University Wonju College of Medicine Department of Internal Medicine Devision of Gastroenterology and Hepatology

More Information

Publications:

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. Epub 2009 Feb 9.

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.

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.

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. No abstract available.

Responsible Party:	Soon Koo Baik/ Yonsei University Wonju College of Medicine Department of Internal Medicine Devision of Gastroenterology and Hepatology, Yonsei University Wonju College of Medicine Department of Internal Medicine Devision of Gastroenterology and Hepatology
ClinicalTrials.gov Identifier:	NCT00990639 History of Changes
Other Study ID Numbers:	YWhep091
Study First Received:	October 6, 2009
Last Updated:	October 6, 2009
Health Authority:	Korea: Institutional Review Board Korea: Food and Drug Administration

Keywords provided by Yonsei University:

hepatic fibrosis
angiotensin II blocking agents
alcoholic liver disease

Additional relevant MeSH terms:

Fibrosis
Liver Diseases
Liver Diseases, Alcoholic
Liver Cirrhosis
Pathologic Processes
Digestive System Diseases
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Ursodeoxycholic Acid
Candesartan

Candesartan cilexetil
Cholagogues and Choleretics
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2013