Beta-blockers for Oesophageal Varices (BOPPP)

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

To determine if carvedilol reduces the rate of variceal haemorrhage in patients with cirrhosis and small oesophageal varices

Study Overview

• Status: Recruiting
• Conditions: Cirrhoses, Liver; Oesophageal Varices
• Intervention / Treatment: Drug: Carvedilol

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.

The investigators know that when varices are large, treatment can be initiated with medication called beta-blockers to reduce the pressure in the varices. If the varices are small, the medical community is not sure if treatment with beta-blockers will work. 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. Research sites will observe patients 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. Research sites 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. Patient will also be notified on the trial results at the end of the study. The barriers and facilitators in adjusting the dose of the tablets to optimise treatment effects primary care will be along with patients' views on taking part in the trial, and whether the side effects justify the potential benefits of reducing the risk of bleeding. The investigators estimate this risk could be reduced from 20% of patients having significant bleeding to 10% over 3 years.

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

Finally, the results of the study will be published 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 Type: Interventional
• Enrollment (Anticipated): 1200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Vishal Patel, BSc, MBBS, MRCP, MPhil; Phone Number: +44 (0)20 3299 3654; Email: vishal.patel@nhs.net
• Study Contact Backup: Name: Kieran Brack, BSc, PhD; Phone Number: +44 (0)20 3299 7142; Email: kch-tr.boppptrial@nhs.net

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B15 2TT
    • Not yet recruiting
    • Queen Elizabeth Hospital
    • Contact: Emma Burke; Phone Number: 0121 3718451; Email: Emma.Burke@uhb.nhs.uk
    • Contact: Phone Number: 07770 827573
    • Principal Investigator: Dhiraj Tripathi, MBChB, MD
  • London, United Kingdom, E1 1FR
    • Not yet recruiting
    • Royal London Hospital (Barts)
    • Contact: James Hand; Phone Number: 020 3594 6773; Email: James.Hand@nhs.net
    • Principal Investigator: Vikram Sharma, MBBS, MRCP, PhD, FRCP
  • London, United Kingdom
    • Recruiting
    • King's College Hosptial NHS Foundation Trust (Denmark Hill)
    • Contact: Ruhuma Uddin, BSc; Phone Number: 020 3299 7142; Email: kch-tr.boppptrial@hs.uk
    • Principal Investigator: Mark McPhail
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT12 6BA
      • Not yet recruiting
      • Royal Victoria Hospital
      • Contact: Angela Toner; Phone Number: 028 90633197; Email: angela.toner@belfasttrust.hscni.net
      • Principal Investigator: Roger McCorry, MB BCh BAO, MRCP

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:

1. Age >18 years

2. Cirrhosis and portal hypertension, defined by any 2 of the following:

   A) Characteristic clinical examination findings; one or more of i) liver function tests ii) haematological panel iii) coagulation profile abnormalities B) Characteristic radiological findings; one or more of i) heterogeneous, small liver with irregular contour ii) splenomegaly iii) ascites iv) varices v) recanalized umbilical vein C) Fibrosis score > stage 4 on liver biopsy D) FibroScan liver stiffness measurement >15 kilo Pascal without other explanation

3. Small oesophageal varices diagnosed within the last 3 months,- defined as <5 mm in diameter or varices which completely disappear on moderate insufflation at gastroscopy.
4. Not received a beta-blocker in the last week
5. Capacity to provide informed consent

Exclusion Criteria:

1. Non-cirrhotic portal hypertension
2. Medium/large oesophageal varices (current or history of), defined as >5 mm in diameter
3. Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding
4. Previous variceal haemorrhage
5. Red signs accompanying varices at endoscopy
6. Known intolerance to beta blockers
7. Contraindication to beta blocker use i) Heart rate <50 bpm ii) Known 2nd degree or higher heart block iii) Sick sinus syndrome iv) Systolic blood pressure <85 mm Hg v) Chronic airways obstruction (asthma/COPD) vi) Floppy Iris Syndrome vii) CYP2D6 Poor Metaboliser viii) History of cardiogenic shock ix) History of severe hypersensitivity reaction to beta-blockers x) Untreated phaeochromocytoma xi) Severe peripheral vascular disease xii) Prinzmetal angina xiii) New York Heart Association IV heart failure
8. Unable to provide informed consent
9. Child Pugh C cirrhosis
10. Already receiving a beta-blocker for another reason that cannot be discontinued
11. Graft cirrhosis post liver transplantation
12. Evidence of active malignancy without curative therapy planned
13. Pregnant or lactating women
14. Women of child bearing potential not willing to use adequate contraception during the protocol of IMP dosing
15. Patients who have been on a CTIMP within the previous 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Carvedilol; 6.25 mg or 12.5 mg if tolerated	Drug: Carvedilol; Oral tablet
Placebo Comparator: Oral Placebo	Drug: Carvedilol; Oral tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variceal bleeding	Time to first variceal haemorrhage	3 years
Health Economic assessment	Assess the cost effectiveness of early intervention with non specific beta blockers in this patient population.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variceal bleed rate	Number of variceal bleeds by allocation	1 and 3 years
Variceal bleeding needing intervention	Number of patients that progress to medium/large varices requiring clinical intervention	3 years
Composite of variceal bleed rate and bleeding needing intervention	Composite of variceal bleed rate and bleeding needing intervention. i.e. Unit less measure of rate of ((Number of patients who bled) PLUS (Number of patients who progressed without bleeding)) / (Number of patients in that arm at randomisation) at 3 years ranging from 0 to 1	3 years
Clinical decompensation	Number of patients with clinical decompensation (spontaneous bacterial peritonitis, new ascites, new hepatic encephalopathy) in the active and inactive IMP groups	3 years
Child Pugh Score for Cirrhosis mortality	Child Pugh Score for Cirrhosis mortalityin the active and inactive IMP groups. Range 5-15. Higher scores represent worse outcomes.	3 years
Model for end-stage liver disease (MELD) score	MELD score in the active and inactive IMP groups.Range 6-40. Higher scores represent worse outcomes.	3 years
Survival (Overall, liver related, cardio-vascular related)	Survival (Overall, liver related, cardio-vascular related)	3 years
Quality of life assessment	Quality of life score using EQ5D-5L in the active and inactive IMP groups. Range 5-25. Higher scores represent worse outcomes.	3 years

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Collaborators: King's College London; Cardiff University; Guy's and St Thomas' NHS Foundation Trust; Brighton and Sussex University Hospitals NHS Trust; St George's University Hospitals NHS Foundation Trust
• Investigators: Study Director: Mark McPhail, BSc, PhD, MB ChB, King's College Hospital NHS Trust; Study Director: Ben Carter, BSc, PhD, King's College London

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2019
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: November 30, 2018
• First Submitted That Met QC Criteria: December 13, 2018
• First Posted (Actual): December 17, 2018

Study Record Updates

• Last Update Posted (Actual): October 3, 2019
• Last Update Submitted That Met QC Criteria: October 1, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Gastrointestinal Diseases; Liver Diseases; Fibrosis; Esophageal Diseases; Hypertension, Portal; Liver Cirrhosis; Esophageal and Gastric Varices; Varicose Veins; 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: 125861

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: To be decided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No