Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of Oesophageal Varices Trial.

Sponsor

King's College Hospital NHS Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT05872698

Collaborator

King's College London (Other), Cardiff University (Other), Brighton and Sussex University Hospitals NHS Trust (Other)

1,200

Enrollment

Location

Arms

Anticipated Duration (Months)

13.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Research has proven that large varices can be treated with beta-blockers (a type of anti-hypertensive medication) to reduce the pressure in the veins. The management of small varices is still uncertain. This study aims to discover if beta blockers can be used in this setting. We hypothesize that beta blockers will reduce the risk of bleeding from small varices from 20% to 10% over a period of 3 years, resulting in significant cost savings to the NHS from better patient outcomes.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis, Liver Portal Hypertension Variceal Hemorrhage Varices, Esophageal	Drug: Carvedilol Drug: Placebo	Phase 4

Detailed Description

Cirrhosis or liver scarring is an important problem in healthcare in the United Kingdom. 60,000 patients are living with this disease and about 11,000 people every year will die because of it. There are several ways in which patients with this severe form of liver disease become unwell or die and bleeding from the oesophagus or stomach is one. Cirrhosis causes pressure changes inside the abdomen and swelling of veins in the oesophagus (called "varices") which can bleed catastrophically.

We know that when varices are large we need to treat them with medication called beta-blockers to reduce the pressure in the varices. If the varices are small, we are not sure if we need to treat with beta-blockers and this study aims to address this uncertainty. Patients who are recruited to the study with small varices will be randomised to either beta-blockers or a placebo. We will observe them closely for 3 years for bleeding from their varices or other complications of cirrhosis or side effects of taking medication. This is the amount of time needed to observe for bleeding when the varices are small. We will review the patients every 6 months including assessing the varices by a camera test called an endoscopy at the beginning and each year until the study is finished.

During the study patients will be involved with the conduct and management of the research, and we will feedback to recruited patients the results at the end. We will assess the barriers and facilitators of doctors in primary care - such as General Practitioners - in adjusting the dose of the tablets to optimise treatment effects, and assess patients' views on taking part in the trial, and whether the side effects justify the potential benefits of reducing the risk of bleeding. We estimate this risk could be reduced from 20% of patients having significant bleeding to 10% over 3 years.

We will measure the impact of beta-blockers on the overall costs to the NHS of caring for people with cirrhosis during the trial. We will then assess the impact of treatment on both mortality and quality of life using a combined measure, the Quality Adjusted Life-Year (QALY). We will use a mathematical prediction model to estimate the impact of treatment on costs, mortality and quality of life over a patient's lifetime. We will assess whether any increased costs are justified by better outcomes for patients and represent good value for money for the NHS budget.

Finally, we will publish the results of the study in the medical literature and discuss the findings at medical conferences, patient groups and with charities involved in helping patients with cirrhosis such as the British Liver Trust.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Triple-blinded

Primary Purpose:

Prevention

Official Title:

Beta-blockers Or Placebo for Primary Prophylaxis of Oesophageal Varices (BOPPP Trial). A Blinded, UK Multi-centre, Clinical Effectiveness and Cost-effectiveness Randomised Controlled Trial.

Actual Study Start Date :

Jun 1, 2019

Anticipated Primary Completion Date :

Dec 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Carvedilol Oral Carvedilol 6.25 mg to 12.5 mg OD/ or 6.25mg BD (maximum dose 12.5mg)	Drug: Carvedilol Carvedilol, sold under the brand name Coreg among others, is a medication used to treat high blood pressure, congestive heart failure, and left ventricular dysfunction in people who are otherwise stable. For high blood pressure, it is generally a second-line treatment. It is taken by mouth.
Placebo Comparator: Placebo Oral tablet (1 or 2 tablets)	Drug: Placebo Placebo

Arm

Intervention/Treatment

Active Comparator: Carvedilol

Oral Carvedilol 6.25 mg to 12.5 mg OD/ or 6.25mg BD (maximum dose 12.5mg)

Drug: Carvedilol

Carvedilol, sold under the brand name Coreg among others, is a medication used to treat high blood pressure, congestive heart failure, and left ventricular dysfunction in people who are otherwise stable. For high blood pressure, it is generally a second-line treatment. It is taken by mouth.

Placebo Comparator: Placebo

Oral tablet (1 or 2 tablets)

Drug: Placebo

Placebo

Outcome Measures

Primary Outcome Measures

Variceal Haemorrhage [3 years from recruitment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18 years and over
Cirrhosis and portal hypertension,
Small oesophageal varices diagnosed within the last 6 months, defined as ≤5 mm in diameter or varices which completely disappear on moderate insufflation at gastroscopy.
Not received a beta-blocker in the last week
Capacity to provide informed consent

Exclusion Criteria:

Non-cirrhotic portal hypertension
Medium/large oesophageal varices (current or history [decreasing in size without curative therapy]), defined as >5 mm in diameter
Gastric (IGV and GOV2), duodenal, rectal varices with or without evidence of recent bleeding.
Previous variceal haemorrhage
Previous band ligation or glue injection of oesophageal and/or gastric varices
Red signs accompanying varices at endoscopy
Known intolerance to beta blockers
Contraindications to beta blocker use
Unable to provide informed consent
Child Pugh C cirrhosis
Already receiving a beta-blocker for another reason that cannot be discontinued
Graft cirrhosis post liver transplantation
Evidence of active malignancy without curative therapy planned
Pregnant or lactating women
Women of child bearing potential not willing to use adequate contraception during the period of IMP dosing
Patients who have been on a CTIMP within the previous 3 months
Clinical symptoms consistent with COVID-19