NCT00006398

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).

Trial Health

90
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
213

participants targeted

Target at P25-P50 for phase_3

Timeline
Completed

Started Aug 1993

Longer than P75 for phase_3

Geographic Reach
3 countries

5 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

August 1, 1993

Completed
7.2 years until next milestone

First Submitted

Initial submission to the registry

October 5, 2000

Completed
1 day until next milestone

First Posted

Study publicly available on registry

October 6, 2000

Completed
1.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 1, 2002

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

September 1, 2002

Completed
Last Updated

June 1, 2017

Status Verified

May 1, 2017

Enrollment Period

9.1 years

First QC Date

October 5, 2000

Last Update Submit

May 30, 2017

Conditions

Esophageal and Gastric VaricesLiver CirrhosisPortal Hypertension

Keywords

cirrhosisesophageal varicesvariceal hemorrhagebeta-adrenergic blocker

Outcome Measures

Primary Outcomes (1)

  • Varices

    Development of varices

    6 years

Study Arms (2)

Timolol Maleate

EXPERIMENTAL

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

Drug: Timolol Maleate

Placebo

PLACEBO COMPARATOR

Timelol placebo

Drug: Placebo

Interventions

Timolol MaleateDRUG
Timolol Maleate
PlaceboDRUG
Placebo

Eligibility Criteria

Age18 Years - 75 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (5)

Yale University Sch. of Medicine

New Haven, Connecticut, 06520, United States

Location

VA CT Healthcare System

West Haven, Connecticut, 06516, United States

Location

The Faulkner Hospital

Boston, Massachusetts, 02130, United States

Location

Hospital Clinic I Provincial de Barcelona

Barcelona, Catalonia, Spain

Location

Royal Free Hospital

Hampstead, London, NW32QG, United Kingdom

Location

Related Publications (4)

  • 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.

    PMID: 1900306BACKGROUND

  • 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.

    PMID: 9178694BACKGROUND

  • 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.

    PMID: 16306522RESULT

  • 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.

    PMID: 19303163DERIVED

MeSH Terms

Conditions

Esophageal and Gastric VaricesLiver CirrhosisHypertension, PortalFibrosis

Interventions

Timolol

Condition Hierarchy (Ancestors)

Esophageal DiseasesGastrointestinal DiseasesDigestive System DiseasesLiver DiseasesPathologic ProcessesPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

PropanolaminesAmino AlcoholsAlcoholsOrganic ChemicalsPropanolsAminesThiadiazolesThiazolesSulfur CompoundsAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsMorpholinesOxazines

Study Officials

  • Roberto J Groszmann, M.D.

    Yale University School of Med.

    PRINCIPAL INVESTIGATOR

  • 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

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
PREVENTION
Intervention Model
PARALLEL
Sponsor Type
NIH
Responsible Party
SPONSOR

Study Record Dates

First Submitted

October 5, 2000

First Posted

October 6, 2000

Study Start

August 1, 1993

Primary Completion

September 1, 2002

Study Completion

September 1, 2002

Last Updated

June 1, 2017

Record last verified: 2017-05

Locations

ES(1)US(3)GB(1)