Prevention of Esophageal Varices by Beta-Adrenergic Blockers

NCT ID: NCT00006398

Last Updated: 2017-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 213 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1993-08-31
• Study Completion Date: 2002-09-30

Brief 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).

Conditions

Esophageal and Gastric Varices; Liver Cirrhosis; Portal Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Timolol Maleate

Dose titrated from 5 mg per day to up to 80 mg per day depending on heart rate

Group Type: EXPERIMENTAL

Timolol Maleate

Intervention Type: DRUG

Placebo

Timelol placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Timolol Maleate

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Eligibility 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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Yale University

OTHER

Sponsor Role: collaborator

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

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roberto J Groszmann, M.D.

Role: PRINCIPAL_INVESTIGATOR

Yale University School of Med.

Norman Grace, M.D.

Role:

Tufts University

Jaime Bosch, M.D.

Role:

University of Barcelona

Andrew Burroughs, M.D.

Role:

University of London

Guadalupe Garcia-Tsao, M.D.

Role:

Yale University

Locations

Yale University Sch. of Medicine

New Haven, Connecticut, United States

VA CT Healthcare System

West Haven, Connecticut, United States

The Faulkner Hospital

Boston, Massachusetts, United States

Hospital Clinic I Provincial de Barcelona

Barcelona, Catalonia, Spain

Royal Free Hospital

Hampstead, London, United Kingdom

Countries

United States; Spain; United Kingdom

References

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. doi: 10.1172/JCI115062.

Reference Type: BACKGROUND

PMID: 1900306 (View on PubMed)

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. doi: 10.1053/gast.1997.v112.pm9178694.

Reference Type: BACKGROUND

PMID: 9178694 (View on PubMed)

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. doi: 10.1056/NEJMoa044456.

Reference Type: RESULT

PMID: 16306522 (View on PubMed)

Ripoll C, Groszmann RJ, Garcia-Tsao G, Bosch J, Grace N, Burroughs A, Planas R, Escorsell A, Garcia-Pagan JC, Makuch R, Patch D, Matloff DS; Portal Hypertension Collaborative Group. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol. 2009 May;50(5):923-8. doi: 10.1016/j.jhep.2009.01.014. Epub 2009 Mar 5.

Reference Type: DERIVED

PMID: 19303163 (View on PubMed)

Other Identifiers

R01DK046580

Identifier Type: NIH

Identifier Source: secondary_id

View Link

YALESM 6618

Identifier Type: OTHER

Identifier Source: secondary_id

Timolol (completed)

Identifier Type: -

Identifier Source: org_study_id

NCT00004641

Identifier Type: -

Identifier Source: nct_alias