Prevention of Esophageal Varices by Beta-Adrenergic Blockers

This study has been completed.

First Received: October 5, 2000 Last Updated: May 4, 2006 History of Changes

Sponsor:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:	NCT00006398

Purpose

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).

Condition	Intervention	Phase
Esophageal and Gastric Varices Liver Cirrhosis Portal Hypertension	Drug: Timolol Maleate	Phase III

Study Type:	Interventional
Study Design:	Prevention, Double-Blind
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

Resource links provided by NLM:

MedlinePlus related topics: Cirrhosis Esophagus Disorders High Blood Pressure Liver Diseases Varicose Veins

Drug Information available for: Timolol Timolol maleate

U.S. FDA Resources

Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Study Start Date:	August 1993
Estimated Study Completion Date:	March 1998

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00006398

Locations

United States, Connecticut
VA CT Healthcare System
West Haven, Connecticut, United States, 06516
Yale University Sch. of Medicine
New Haven, Connecticut, United States, 06520
United States, Massachusetts
The Faulkner Hospital
Boston, Massachusetts, United States, 02130
Spain, Catalonia
Hospital Clinic I Provincial de Barcelona
Barcelona, Catalonia, Spain
United Kingdom, London
Royal Free Hospital
Hampstead, London, United Kingdom, NW32QG

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

Principal Investigator:	Roberto J Groszmann, M.D.	Yale University School of Med.
Investigator:	Norman Grace, M.D.	Tufts University
Investigator:	Jaime Bosch, M.D.	University of Barcelona
Investigator:	Andrew Burroughs, M.D.	University of London
Investigator:	Guadalupe Garcia-Tsao, M.D.	Yale University

More Information

Publications:

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 cirrhosis. N Engl J Med. 2005 Nov 24;353(21):2254-61.

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.

Escorsell A, Ferayorni L, Bosch J, Garcia-Pagan JC, Garcia-Tsao G, Grace ND, Rodes 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.

Study ID Numbers:	Timolol, RO1 DK46580, YALESM, 6618
Study First Received:	October 5, 2000
Last Updated:	May 4, 2006
ClinicalTrials.gov Identifier:	NCT00006398 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

cirrhosis
esophageal varices
variceal hemorrhage
beta-adrenergic blocker

Additional relevant MeSH terms:

Liver Diseases
Neurotransmitter Agents
Adrenergic Agents
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Diseases
Fibrosis
Physiological Effects of Drugs
Liver Cirrhosis
Hypertension, Portal
Pathologic Processes
Varicose Veins
Therapeutic Uses
Adrenergic beta-Antagonists

Cardiovascular Diseases
Timolol
Anti-Arrhythmia Agents
Vascular Diseases
Cardiovascular Agents
Antihypertensive Agents
Pharmacologic Actions
Digestive System Diseases
Esophageal and Gastric Varices
Adrenergic Antagonists
Esophageal Diseases
Hypertension

ClinicalTrials.gov processed this record on November 27, 2009