A Study to Prevent Complications of High Blood Pressure Caused by Hepatitis in Patients With Cirrhosis

Condition(s) targeted: Hypertension, Portal; Liver Cirrhosis; Esophageal and Gastric Varices

Intervention: timolol (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Official(s) and/or principal investigator(s):
Robert J. Groszmann, Study Chair, Affiliation: Yale University

OBJECTIVES:

I. Evaluate the efficacy of a certain drug in preventing intestinal complications in patients with cirrhosis and high blood pressure in the hepatic portal vein.

II. Evaluate vein pressure measurements to predict the development of internal bleeding.

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 design: Prevention, Randomized, Double-Blind, Placebo Control, Efficacy Study

Detailed description: PROTOCOL OUTLINE: This is a randomized, double-blind study. Patients are stratified by participating institution, cirrhosis etiology, and hepatic venous pressure gradient.

The dose of oral timolol is titrated over 28 days. Patients are then randomly assigned to daily timolol at the titrated dose or a placebo if successful titration is achieved by day 28, and the final titration dose is maintained for at least 10 days. Timolol is discontinued prior to randomization.

Criteria for removal from study include esophageal or gastric varices, significant bleeding or hemorrhage, timolol-induced hepatic encephalopathy, and liver transplantation.

Patients are followed every 3 months.

Minimum age: 18 Years. Maximum age: 74 Years. Gender(s): Both.

Criteria:

- Biopsy-proven cirrhosis of any etiology, including hepatitis B or C. No primary

biliary cirrhosis.

- Hepatic venous pressure gradient (HVPG) at least 6 mm Hg.

- Histologic slides available for review OR liver-spleen scan compatible with cirrhosis

if biopsy older than 5 years. Repeat biopsy required if scan incompatible OR HVPG at least 10 mm Hg and any of the following clinical features suggestive of cirrhosis: telangiectasias, palmar erythema, muscle wasting, liver hard and nodular, or splenomegaly, hypoalbuminemia, hyperbilirubinemia, or prolonged prothrombin time, liver-spleen scan with colloid shift to spleen or bone marrow, collaterals visualized by ultrasound or CT.

- Gastroesophageal varices negative by endoscopy within 3 months prior to

randomization.

- Independent verification by 2 endoscopists required.

- No ascites requiring specific treatment, e. g., diuretics, paracentesis,

peritoneovenous shunt.

- Ascites controlled by salt restriction alone allowed.

- No splenic or portal vein thrombosis by Doppler-ultrasound.

- No primary sclerosing cholangitis.

- No radiologically or histologically proven hepatocellular carcinoma.

Prior/Concurrent Therapy

- At least 1 month since participation in another pharmacologic clinical trial.

- At least 1 month since drugs that may affect splanchnic hemodynamics or portal

pressure, e. g., beta-blockers, clonidine prazosin, nitrates molsidomine

Patient Characteristics

- Life expectancy: At least 1 year

- Other: Eligibility determined on an individual basis for the following: aortic valve

stenosis, atrioventricular block, asthma, chronic obstructive pulmonary disease with positive bronchoconstrictive test, heart failure, hypersensitivity to beta-blockers, insulin-dependent diabetes, organic psychosis, peripheral vascular disease.

- No alcohol intake during titration period.

- No pregnant women.

- Effective contraception required of fertile women.

Yale University School of Medicine, New Haven, Connecticut 06510, United States

Related publications:

Wongcharatrawee S, Groszmann RJ. Diagnosing portal hypertension. Baillieres Best Pract Res Clin Gastroenterol. 2000 Dec;14(6):881-94. Review.

Starting date: May 1993
Last updated: June 23, 2005