Prevention of Esophageal Varices by Beta-Adrenergic Blockers

May 30, 2017 updated by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

213

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Varices
Time Frame: 6 years
Development of varices
6 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

Yale University

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 1993

Primary Completion (Actual)

September 1, 2002

Study Completion (Actual)

September 1, 2002

Study Registration Dates

First Submitted

October 5, 2000

First Submitted That Met QC Criteria

October 5, 2000

First Posted (Estimate)

October 6, 2000

Study Record Updates

Last Update Posted (Actual)

June 1, 2017

Last Update Submitted That Met QC Criteria

May 30, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Timolol (completed)
  • R01DK046580 (U.S. NIH Grant/Contract)
  • YALESM 6618 (Other Identifier: Yale School of Medicine)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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