Prevention of Esophageal Varices by Beta-Adrenergic Blockers

Study Overview
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Brief Summary
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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).

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

Conditions
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Esophageal and Gastric Varices, Liver Cirrhosis, Portal Hypertension

Intervention / Treatment
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* Drug: Timolol Maleate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Timolol Maleate<br>Dose titrated from 5 mg per day to up to 80 mg per day depending on heart rate | Drug: Timolol Maleate<br> <br> |
| Placebo Comparator: Placebo<br>Timelol placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Varices | Development of varices | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cirrhosis, esophageal varices, variceal hemorrhage, beta-adrenergic blocker