Clinical trial NCT00006398: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Esophageal and Gastric Varices
Liver Cirrhosis
Portal Hypertension
Keywords: cirrhosis
esophageal varices
variceal hemorrhage
beta-adrenergic blocker
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: Yale University
First posted: 2000-10-06
Enrollment: 213
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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).


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.

Primary outcomes:
measure: Varices
timeFrame: 6 years
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University Sch. of Medicine
state: Connecticut
city: West Haven
country: United States
facility: VA CT Healthcare System
state: Connecticut
city: Boston
country: United States
facility: The Faulkner Hospital
state: Massachusetts
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial de Barcelona
state: Catalonia
city: Hampstead
country: United Kingdom
facility: Royal Free Hospital
state: London
Study officials:
affiliation: Yale University School of Med.
name: Roberto J Groszmann, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts University
name: Norman Grace, M.D.
affiliation: University of Barcelona
name: Jaime Bosch, M.D.
affiliation: University of London
name: Andrew Burroughs, M.D.
affiliation: Yale University
name: Guadalupe Garcia-Tsao, M.D.
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.