Effect of Candesartan in Alcoholic Liver Fibrosis

NCT00990639 | Completed Phase 1 DMC

• 1 other identifier: YWhep091
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Alcoholic Liver Disease

Keywords

hepatic fibrosis; angiotensin II blocking agents; alcoholic liver disease

Outcome Measures

Primary Outcomes (1)

• Improvement of histologic grade of hepatic fibrosis

  6 month later

Secondary Outcomes (1)

• estimation of safety of candesartan in hepatic fibrosis

  6 month later

Study Arms (2)

candesartan+UDCA group

EXPERIMENTAL

oral candesartan(8 mg/day) in addition to ursodeoxycholic acid (UDCA, 600 mg/day) for 6 months

Drug: candesartan for hepatic fibrosis

UDCA group

PLACEBO COMPARATOR

ursodeoxycholic acid(UDCA,600 mg/day)only for 6 months

Drug: candesartan for hepatic fibrosis

Interventions

candesartan for hepatic fibrosis DRUG

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

Also known as: atacand for hepatic fibrosis

UDCA group; candesartan+UDCA group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Yonsei University: lead

Study Sites (1)

Yonsei University Wonju College of Medicine Wonju Christian Hospital

Wŏnju, Gangwon-do, 220-701, South Korea

Location

Related 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.

  PMID: 19220742 BACKGROUND

• Rimola A, Londono MC, Guevara G, Bruguera M, Navasa M, Forns X, Garcia-Retortillo M, Garcia-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. doi: 10.1097/01.tp.0000128913.09774.ce.

  PMID: 15371669 BACKGROUND

• 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. doi: 10.1016/j.jhep.2007.01.017. Epub 2007 Feb 9.

  PMID: 17336417 BACKGROUND

• 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. doi: 10.1053/jhep.2002.32679. No abstract available.

  PMID: 12297856 BACKGROUND

MeSH Terms

Conditions

Liver Diseases, Alcoholic; Liver Cirrhosis

Interventions

candesartan; candesartan cilexetil

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Soon Koo Baik, Professor

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: October 6, 2009
• First Posted: October 7, 2009
• Study Start: September 1, 2005
• Primary Completion: December 1, 2008
• Study Completion: March 1, 2009
• Last Updated: October 7, 2009

Record last verified: 2009-10

Locations

KR (1)