Prevention of Esophageal Varices by Beta-Adrenergic Blockers

Liver Cirrhosis Clinical Trial

Official title:

Randomized, Double-Blind Study of Timolol (A Nonselective Beta-Adrenergic Blocker) vs Placebo to Prevent Complications of Hepatic Portal Hypertension in Patients With Cirrhosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00006398
• Other study ID #: Timolol (completed)
• Secondary ID: R01DK046580YALES
• Status: Completed
• Phase: Phase 3
• First received: October 5, 2000
• Last updated: May 30, 2017
• Start date: August 1993
• Est. completion date: September 2002

Study information

• Verified date: May 2017
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to learn whether timolol is useful in preventing or delaying the appearance of gastroesophageal varices, a complication that may develop in the future as a consequence of liver disease. Cirrhosis causes an increased resistance of blood flowing through the liver. This leads to an increased pressure in the portal vein (the vein that takes blood to your liver). High portal pressure is responsible for the appearance of complications of chronic liver disease such as varices and variceal bleeding (bleeding from veins in your esophagus). Timolol belongs to a group of medications called beta-blockers. Beta-blockers decrease high portal pressure and previous studies have shown that beta-blocker pills are useful in preventing bleeding from varices in patients who already have varices. A more desirable effect would be if these pills could prevent not only bleeding from varices but the appearance of varices (and therefore of bleeding).

Other known NCT identifiers

• NCT00004641

Recruitment information / eligibility

• Status: Completed
• Enrollment: 213
• Est. completion date: September 2002
• Est. primary completion date: September 2002
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Liver biopsy compatible with cirrhosis.

• Absence of gastroesophageal varices.

• An increased hepatic venous pressure gradient (HVPG) (6mmHg).

• Age over 18 and below 76 years.

• Informed, written consent.

• Absence of exclusion criteria.

Exclusion Criteria:

• Presence of ascites that requires specific treatment (diuretics, paracentesis, peritoneo-venous shunt, etc).

• Proven hepatocellular carcinoma by radiological or histological criteria.

• Splenic or portal vein thrombosis by Doppler-ultrasound.

• Presence of any concurrent disease that is expected to decrease life expectancy to less than one year.

• Patients taking diuretics, beta-blockers, clonidine, prazosin, nitrates, molsidomine and any drug which may have an effect on splanchnic hemodynamics/portal pressure.

• Patients participating in other pharmacological randomized clinical trials.

• Patients with primary biliary cirrhosis and primary sclerosing cholangitis will also be excluded since these entities have a slower progression of the disease, are usually enrolled in other clinical trials and are transplanted at an earlier stage.

• Contraindications to beta-blockers: asthma, COPD with positive broncoconstrictive test, heart failure, A-V block, aortic valve stenosis, organic psychosis, insulin-dependent diabetes, hypersensitivity to beta-blockers.

• Women who are pregnant, nursing or of childbearing potential and who are not using oral or mechanical contraception.

Related Conditions & MeSH terms

• Esophageal and Gastric Varices
• Fibrosis
• Hypertension
• Hypertension, Portal
• Liver Cirrhosis
• Portal Hypertension

Intervention

Drug:
• Timolol Maleate

• Placebo

Locations

Country	Name	City	State
Spain	Hospital Clinic I Provincial de Barcelona	Barcelona	Catalonia
United Kingdom	Royal Free Hospital	Hampstead	London
United States	The Faulkner Hospital	Boston	Massachusetts
United States	Yale University Sch. of Medicine	New Haven	Connecticut
United States	VA CT Healthcare System	West Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	Yale University

Countries where clinical trial is conducted

United States,  Spain,  United Kingdom, 

References & Publications (3)

Escorsell A, Ferayorni L, Bosch J, García-Pagán JC, García-Tsao G, Grace ND, Rodés J, Groszmann RJ. The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices. Gastroenterology. 1997 Jun;112(6):2012-6. — View Citation

Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Gao H, Makuch R; Portal Hypertension Collaborative Group.. Beta-blockers to prevent gastroesophageal varices in patients with cirrho — View Citation

Sarin SK, Groszmann RJ, Mosca PG, Rojkind M, Stadecker MJ, Bhatnagar R, Reuben A, Dayal Y. Propranolol ameliorates the development of portal-systemic shunting in a chronic murine schistosomiasis model of portal hypertension. J Clin Invest. 1991 Mar;87(3):1032-6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Varices	Development of varices	6 years