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Prevention of Esophageal Varices by Beta-Adrenergic Blockers

This study has been completed.
Sponsor:
Collaborator:
Yale University
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT00006398
First received: October 5, 2000
Last updated: May 30, 2017
Last verified: May 2017
  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 Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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:


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

Primary Outcome Measures:
  • Varices [ Time Frame: 6 years ]
    Development of varices


Enrollment: 213
Actual Study Start Date: August 1993
Study Completion Date: September 2002
Primary Completion Date: September 2002 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
United States, Connecticut
Yale University Sch. of Medicine
New Haven, Connecticut, United States, 06520
VA CT Healthcare System
West Haven, Connecticut, United States, 06516
United States, Massachusetts
The Faulkner Hospital
Boston, Massachusetts, United States, 02130
Spain
Hospital Clinic I Provincial de Barcelona
Barcelona, Catalonia, Spain
United Kingdom
Royal Free Hospital
Hampstead, London, United Kingdom, NW32QG
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Yale University
Investigators
Principal Investigator: Roberto J Groszmann, M.D. Yale University School of Med.
OverallOfficial: Norman Grace, M.D. Tufts University
OverallOfficial: Jaime Bosch, M.D. University of Barcelona
OverallOfficial: Andrew Burroughs, M.D. University of London
OverallOfficial: Guadalupe Garcia-Tsao, M.D. Yale University
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00006398     History of Changes
Obsolete Identifiers: NCT00004641
Other Study ID Numbers: Timolol (completed)
R01DK046580 ( U.S. NIH Grant/Contract )
YALESM 6618 ( Other Identifier: Yale School of Medicine )
Study First Received: October 5, 2000
Last Updated: May 30, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

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:
Hypertension
Fibrosis
Liver Cirrhosis
Hypertension, Portal
Esophageal and Gastric Varices
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Liver Diseases
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Timolol
Adrenergic beta-Antagonists
Adrenergic Agents
Adrenergic Antagonists
Maleic acid
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 22, 2017