Prevention of Esophageal Varices by Beta-Adrenergic Blockers

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Primary Purpose

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Timolol Maleate

Placebo

About this trial

This is an interventional prevention trial for Esophageal and Gastric Varices focused on measuring cirrhosis, esophageal varices, variceal hemorrhage, beta-adrenergic blocker

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Yale University Sch. of Medicine
VA CT Healthcare System
The Faulkner Hospital
Hospital Clinic I Provincial de Barcelona
Royal Free Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Timolol Maleate

Placebo

Arm Description

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

Timelol placebo

Outcomes

Primary Outcome Measures

Varices

Development of varices

Secondary Outcome Measures

Full Information

NCT ID

NCT00006398

First Posted

October 5, 2000

Last Updated

May 30, 2017

Sponsor

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

Collaborators

Yale University

1. Study Identification

Unique Protocol Identification Number

NCT00006398

Brief Title

Prevention of Esophageal Varices by Beta-Adrenergic Blockers

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Completed

Study Start Date

August 1993 (Actual)

Primary Completion Date

September 2002 (Actual)

Study Completion Date

September 2002 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

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

Collaborators

Yale University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

No

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Esophageal and Gastric Varices, Liver Cirrhosis, Portal Hypertension

Keywords

cirrhosis, esophageal varices, variceal hemorrhage, beta-adrenergic blocker

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

213 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Timolol Maleate

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Timelol placebo

Intervention Type

Drug

Intervention Name(s)

Timolol Maleate

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

Varices

Description

Development of varices

Time Frame

6 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

No

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. 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.

Overall Study Officials: