Carvedilol vs Band Ligation vs Combination Therapy for Primary Prophylaxis of Variceal Bleeding

A Phase 3 Study of Carvedilol vs Variceal Band Ligation vs Combination Therapy for Primary Prophylaxis of Variceal Bleeding

Subjects will be those individuals greater than 18 years of age with a diagnosis of cirrhosis undergoing screening for esophageal varices. Eligible subjects will have a diagnosis of cirrhosis and esophageal varices (graded as medium or large) with no prior history of variceal bleeding. The diagnosis of cirrhosis will be based on clinical, radiologic, and/or laboratory data. Patients will be randomly assigned using electronic medical records to one of three treatment arms after screening esophagogastroduodenoscopy (EGD) has been performed and large varices are identified. Primary outcome of the study will be the incidence of variceal bleeding in patients receiving one of the following therapies for primary prophylaxis of variceal bleeding: carvedilol, variceal band ligation (VBL), or both carvedilol and VBL.

Study Overview

• Status: Withdrawn
• Conditions: Portal Hypertension Related to Cirrhosis
• Intervention / Treatment: Drug: Carvedilol; Procedure: Variceal band ligation

Detailed Description

Inclusion criteria for the study will be an individual > 18 years old with a diagnosis of cirrhosis (either by history, serology or imaging), with medium or large esophageal varices on variceal screening esophagogastroduodenoscopy (EGD), and no prior history of gastrointestinal (GI) bleeding, as related to portal hypertension. Exclusion criteria will be the following: pregnant females; patients on beta blockers or nitrates for any underlying condition; allergies to carvedilol; mean arterial pressure < 55 mm Hg or pulse < 55 beats per minute at baseline; presence of hepatocellular carcinoma; presence of portal vein thrombosis; patients with severe, uncontrolled respiratory disease (asthma, COPD); patients with complete heart block or other significant arrhythmias; those with significant renal disease (CKD stage III or higher); patients who are unable to provide consent; and patients who in the opinion of the principal investigator are not suitable for participation in the trial.

Patients will be randomized to one of the following three treatment groups: (1) carvedilol group, (2) variceal band ligation and (3) combination therapy (carvedilol plus variceal band ligation). Since the standard of care at University Hospital is use of beta blocker medications, the carvedilol group will serve as the control group.

After consent has been obtained for the EGD and research study and patients have met the non-endoscopic inclusion and exclusion criteria mentioned above, they will undergo a screening EGD to look for varices. Varices will be graded by the 2-group classification system of "small" and "large". Varices are graded as large if > 5mm and small if < 5mm in size. A biopsy forceps will be inserted through the biopsy channel of the gastroscope and opened. An open biopsy forceps measures approximately 5mm in diameter. This will be used to measure the size of the varices and will be confirmed by two physicians. If a patient is found to have small esophageal varices, they will be excluded from the study and managed as per the standard of care. Once a patient has been identified in having large esophageal varices, he or she will undergo randomization during that initial endoscopy. A random number generator will be used to randomize the patient into one of the three treatment groups described above. If a patient is randomized to the carvedilol group, the endoscopic procedure will be terminated and the patient will be given a prescription for carvedilol at the time of discharge. He or she will then be followed up in our Gastroenterology clinics in a regular fashion where medication can be titrated and symptoms can be assessed. If a patient is randomized to the variceal band ligation group, the patient will undergo banding of the esophageal varices with a Wilson-Cook multi-banding device. He/she will be started on a proton-pump inhibitor post-procedure to minimize the risk of post-banding ulcers, a known complication of variceal banding. Once the patient has been treated with VBL, this procedure will be scheduled and repeated every two weeks until the obliteration of varices (ie once varices cannot be detected on endoscopy). The first surveillance EGD after obliteration will then be performed 1-3 months after obliteration and then every 6 months to check for variceal recurrence. If a patient is randomized to the combination group, the patient will undergo the banding protocol described above. The patient will then be given a prescription for carvedilol and a proton-pump inhibitor on discharge and followed in our clinics as scheduled.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers NJ Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Inclusion criteria for the study will be an individual > 18 years old with a diagnosis of cirrhosis (either by history, serology or imaging), with medium or large esophageal varices on variceal screening esophagogastroduodenoscopy (EGD), and no prior history of gastrointestinal (GI) bleeding, as related to portal hypertension

Exclusion Criteria:

• Exclusion criteria will be the following: pregnant females; patients on beta blockers or nitrates for any underlying condition; allergies to carvedilol; mean arterial pressure < 55 mm Hg or pulse < 55 beats per minute at baseline; presence of hepatocellular carcinoma; presence of portal vein thrombosis; patients with severe, uncontrolled respiratory disease (asthma, COPD); patients with complete heart block or other significant arrhythmias; those with significant renal disease (CKD stage III or higher); patients who are unable to provide consent; and patients who in the opinion of the principal investigator are not suitable for participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Carvedilol; Initiating patient on carvedilol after diagnosis of varices made on endoscopy	Drug: Carvedilol; Administering carvedilol to patients diagnosed with large varices on endoscopy; Other Names: Coreg
Active Comparator: Variceal Band Ligation; performing variceal band ligation during endoscopy on patient after diagnosis of esophageal varices made on endoscopy	Procedure: Variceal band ligation; Performing variceal band ligation during endoscopy after diagnosis of large varices on endoscopy
Active Comparator: Combination Group (Carvedilol + Variceal band ligation); once patient has confirmed large esophageal varices on endoscopy, he/she will be started on carvedilol (post-procedure) in addition to having variceal band ligation performed during endoscopy	Drug: Carvedilol; Administering carvedilol to patients diagnosed with large varices on endoscopy; Other Names: Coreg; Procedure: Variceal band ligation; Performing variceal band ligation during endoscopy after diagnosis of large varices on endoscopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of first variceal bleed	within 2 year follow-up period

Secondary Outcome Measures

Outcome Measure	Time Frame
Bleed-related mortality	within 2-year follow-up period
Overall mortality	Within 2 year follow-up period
Recurrence of varices	within 2 year follow-up period

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Investigators: Principal Investigator: NIKOLAOS T PYRSOPOULOS, MD, RUTGERS - NJMS- DEPARTMENT OF MEDICINE

Publications and helpful links

General Publications

• Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W; Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007 Sep;46(3):922-38. doi: 10.1002/hep.21907. No abstract available. Erratum In: Hepatology. 2007 Dec;46(6):2052.

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2018
• Primary Completion (Anticipated): March 1, 2019
• Study Completion (Anticipated): September 1, 2021

Study Registration Dates

• First Submitted: February 17, 2014
• First Submitted That Met QC Criteria: February 17, 2014
• First Posted (Estimate): February 19, 2014

Study Record Updates

• Last Update Posted (Actual): July 24, 2018
• Last Update Submitted That Met QC Criteria: July 20, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: portal hypertension; carvedilol; esophageal varices; variceal bleed; variceal band ligation
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Hypertension; Hypertension, Portal; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol
• Other Study ID Numbers: Pro2013003729

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No