Title: Carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE)
Funder: Department of Health and Social Care

Abstract: Design: A multicentre randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in patients with cirrhosis and medium to large oesophageal varices. There will be an internal pilot and a health economic evaluation. Setting: Gastroenterology/Hepatology Hospital Departments, mainly outpatient clinic and endoscopy settings in England and Scotland. The 66 centres recruiting for the STOPAH trial will be formally approached to participate. The study has been supported by the British Society of Gastroenterology / British Association for the Study of Liver Research Development Group and NIHR Hepatology Clinical Specialty Leads. The trial information has been distributed nationally and has been informally supported by the members of the specialist societies. Target populations: Patients aged 18 and over with liver cirrhosis and medium to large varices that have never bled. Exclusions: Pregnant or lactating patients; contraindications to beta-blockers; presence of malignancy that is likely to affect survival; patients unable to provide informed consent; patients with known hypotension; acute alcoholic hepatitis. Health technologies: Carvedilol and variceal band ligation, which are currently both recommended treatments. Sample Size: 2630 patients (1:1 randomisation) based on a superiority hypothesis with power 90%, alpha 0.05 and allowing for 10% dropout. Study Duration: 6 months set up,4 years for recruitment including 12 month pilot phase, 1 year follow up and 9 months analysis and reporting. Expertise of the team: Leading clinical experts in the field who have conducted similar research in the past. The Clinical Trials Unit comprises the Director, statistician, and trial coordinators, with links to health economist and trial coordinators.

Lay abstract: The problem Liver disease is the 5th biggest killer in the UK. Nearly 12,000 people die of liver disease every year in England. The latest statistics show that 30,000 – 60,000 people in England are at risk of or already have liver cirrhosis (scarring of the liver). Between 1999-2009, 5 times as many 35-55 year olds have developed cirrhosis. Liver cirrhosis leads to the development of enlarged and unwelcome veins (called varices) in the lower oesophagus (gullet). There are over 2500 patients with cirrhosis and varices in England each year. Such patients have a 1 in 20 chance in any year of such veins bleeding which in severe cases could result in death. It is therefore important to lower the risk of variceal bleeding. Current treatments There are two treatments to lower the risk of bleeding. 1. Beta-blocker drugs At the moment propranolol or carvedilol pills are used. Beta-blockers slow down the heart rate and lower blood pressure. The result is lower pressure in the varices which reduces the risk of bleeding. 2. Variceal banding A flexible tube (endoscope) incorporating a light, a miniature video camera and carrying a rubber ring is passed through the mouth to the gullet. An enlarged vein can be tied off with the rubber ring. Repeated endoscopies are required. Clinical trials appear to show that banding is more effective than beta-blockers in lowering the risk of variceal bleeding, although in high quality trials both treatments work just about the same. Overall survival rates are the same for both treatments. Side effects with beta-blockers are mostly minor. Banding has fewer side effects, but they are much more serious; banding can cause bleeding and death. The cost of beta-blockers can be less than £1 per month of treatment whereas banding can cost over £1200 to complete treatment. Our clinical trial But what about carvedilol? It’s better than propranolol at lowering the pressure in the veins (the lower the pressure, the lower the risk of bleeding). Patients tolerate it well, and it’s cheaper. There are only 2 small clinical trials comparing carvedilol with banding in patients with medium to large varices with inconsistent results. Nobody so far has compared carvedilol and banding in a large clinical trial. So, carvedilol seems the ideal drug to compare with banding in a new large clinical trial. Our team has a lot of experience running clinical trials in patients with liver disease. We want to do a trial to compare carvedilol with banding in cirrhosis patients who have medium to large varices that have never bled. Patients will randomly get carvedilol or banding. The main aim is to see if carvedilol is better than banding in lowering the risk of the first variceal bleed from happening (primary prevention). The trial will involve recruiting just over 2,500 patients nationally over 4 years, and would include a 12 month pilot study to ensure everything runs smoothly. We will also look at how both treatments affect the patients’ quality of life, and the cost of the treatments. If it is concluded that carvedilol is found to be more effective than banding, we expect to see a significant change in clinical practice. Patients with cirrhosis and medium to large varices that have not bled will be offered carvedilol instead of banding wherever possible. This will cut the need for endoscopies and banding procedures, with a potential saving of over £1.5 million of NHS resources over a 5 year period

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL