Clinical trial NCT03776955: Beta-blockers for Oesophageal Varices
Official title: Beta-blockers or Placebo for Primary Prophylaxis of Oesophageal Varices (BOPPP Trial). A Blinded, Multi-centre, Clinical Effectiveness and Cost-effectiveness Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Cirrhoses, Liver
Oesophageal Varices
Lead sponsor: King's College Hospital NHS Trust
Sponsor class: OTHER
Collaborators: name: King's College London
name: Guy's and St Thomas' NHS Foundation Trust
name: St George's University Hospitals NHS Foundation Trust
name: Cardiff University
name: Brighton and Sussex University Hospitals NHS Trust
First posted: 2018-12-17
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Variceal bleeding
timeFrame: 3 years
measure: Health Economic assessment
timeFrame: 3 years
Secondary outcomes:
measure: Variceal bleed rate
timeFrame: 1 and 3 years
measure: Variceal bleeding needing intervention
timeFrame: 3 years
measure: Composite of variceal bleed rate and bleeding needing intervention
timeFrame: 3 years
measure: Clinical decompensation
timeFrame: 3 years
measure: Child Pugh Score for Cirrhosis mortality
timeFrame: 3 years
measure: Model for end-stage liver disease (MELD) score
timeFrame: 3 years
measure: Survival (Overall, liver related, cardio-vascular related)
timeFrame: 3 years
measure: Quality of life assessment
timeFrame: 3 years
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital
state: Northern Ireland
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: London
country: United Kingdom
facility: Royal London Hospital (Barts)
city: London
country: United Kingdom
facility: King's College Hosptial NHS Foundation Trust (Denmark Hill)
Study officials:
affiliation: King's College Hospital NHS Trust
name: Mark McPhail, BSc, PhD, MB ChB
role: STUDY_DIRECTOR
affiliation: King's College London
name: Ben Carter, BSc, PhD
role: STUDY_DIRECTOR
References: