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Beta-blockers for Oesophageal Varices (BOPPP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03776955
Recruitment Status : Recruiting
First Posted : December 17, 2018
Last Update Posted : October 3, 2019
Sponsor:
Collaborators:
King's College London
Guy's and St Thomas' NHS Foundation Trust
St George's University Hospitals NHS Foundation Trust
Cardiff University
Brighton and Sussex University Hospitals NHS Trust
Information provided by (Responsible Party):
King's College Hospital NHS Trust

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

Condition or disease Intervention/treatment Phase
Cirrhoses, Liver Oesophageal Varices Drug: Carvedilol 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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Placebo matched control
Primary Purpose: Prevention
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
Actual Study Start Date : June 17, 2019
Estimated Primary Completion Date : September 2024
Estimated Study Completion Date : December 2024


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




Primary Outcome Measures :
  1. Variceal bleeding [ Time Frame: 3 years ]
    Time to first variceal haemorrhage

  2. Health Economic assessment [ Time Frame: 3 years ]
    Assess the cost effectiveness of early intervention with non specific beta blockers in this patient population.


Secondary Outcome Measures :
  1. Variceal bleed rate [ Time Frame: 1 and 3 years ]
    Number of variceal bleeds by allocation

  2. Variceal bleeding needing intervention [ Time Frame: 3 years ]
    Number of patients that progress to medium/large varices requiring clinical intervention

  3. Composite of variceal bleed rate and bleeding needing intervention [ Time Frame: 3 years ]
    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

  4. Clinical decompensation [ Time Frame: 3 years ]
    Number of patients with clinical decompensation (spontaneous bacterial peritonitis, new ascites, new hepatic encephalopathy) in the active and inactive IMP groups

  5. Child Pugh Score for Cirrhosis mortality [ Time Frame: 3 years ]
    Child Pugh Score for Cirrhosis mortalityin the active and inactive IMP groups. Range 5-15. Higher scores represent worse outcomes.

  6. Model for end-stage liver disease (MELD) score [ Time Frame: 3 years ]
    MELD score in the active and inactive IMP groups.Range 6-40. Higher scores represent worse outcomes.

  7. Survival (Overall, liver related, cardio-vascular related) [ Time Frame: 3 years ]
    Survival (Overall, liver related, cardio-vascular related)

  8. Quality of life assessment [ Time Frame: 3 years ]
    Quality of life score using EQ5D-5L in the active and inactive IMP groups. Range 5-25. Higher scores represent worse outcomes.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03776955


Contacts
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Contact: Vishal Patel, BSc, MBBS, MRCP, MPhil +44 (0)20 3299 3654 vishal.patel@nhs.net
Contact: Kieran Brack, BSc, PhD +44 (0)20 3299 7142 kch-tr.boppptrial@nhs.net

Locations
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United Kingdom
Royal Victoria Hospital Not yet recruiting
Belfast, Northern Ireland, United Kingdom, BT12 6BA
Contact: Angela Toner    028 90633197    angela.toner@belfasttrust.hscni.net   
Principal Investigator: Roger McCorry, MB BCh BAO, MRCP         
Queen Elizabeth Hospital Not yet recruiting
Birmingham, United Kingdom, B15 2TT
Contact: Emma Burke    0121 3718451    Emma.Burke@uhb.nhs.uk   
Contact    07770 827573      
Principal Investigator: Dhiraj Tripathi, MBChB, MD         
Royal London Hospital (Barts) Not yet recruiting
London, United Kingdom, E1 1FR
Contact: James Hand    020 3594 6773    James.Hand@nhs.net   
Principal Investigator: Vikram Sharma, MBBS, MRCP, PhD, FRCP         
King's College Hosptial NHS Foundation Trust (Denmark Hill) Recruiting
London, United Kingdom
Contact: Ruhuma Uddin, BSc    020 3299 7142    kch-tr.boppptrial@hs.uk   
Principal Investigator: Mark McPhail         
Sponsors and Collaborators
King's College Hospital NHS Trust
King's College London
Guy's and St Thomas' NHS Foundation Trust
St George's University Hospitals NHS Foundation Trust
Cardiff University
Brighton and Sussex University Hospitals NHS Trust
Investigators
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Study Director: Mark McPhail, BSc, PhD, MB ChB King's College Hospital NHS Trust
Study Director: Ben Carter, BSc, PhD King's College London
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Responsible Party: King's College Hospital NHS Trust
ClinicalTrials.gov Identifier: NCT03776955    
Other Study ID Numbers: 125861
First Posted: December 17, 2018    Key Record Dates
Last Update Posted: October 3, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: To be decided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Cirrhosis
Esophageal and Gastric Varices
Varicose Veins
Fibrosis
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Liver Diseases
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Hypertension, Portal
Carvedilol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Antioxidants
Protective Agents
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists