Carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis

Plain English Summary

Background and study aims
People with long-standing liver disease called cirrhosis (scarring of the liver) can develop enlargement of veins in the gullet (food pipe) known as ‘oesophageal varices’. Patients with medium to large oesophageal varices have a 1 in 3 chance of these veins bleeding. In very severe cases, this could result in death. It is therefore important to lower the risk of this bleeding. At present, all people with medium to large oesophageal varices are offered one of two treatments to lower the risk of bleeding either beta-blockers or variceal band ligation. Some research studies suggest that banding may be more effective than beta-blockers in lowering the risk of variceal bleeding, but other studies suggest that this is not the case. However, all of these studies have been small and we still do not know which treatment is best. We need to do a study to compare carvedilol with banding in people with cirrhosis who have medium to large varices that have never bled. Therefore the aim of the trial is to see which intervention works better. This will be done by observing which treatment is effective in stopping the bleeding of varices in the first 12 months after randomisation.

Who can participate?
Adults who have been diagnosed with liver cirrhosis who have medium or large varices that have not bled

What does the study involve?
Participants will be randomly allocated to receive either beta-blocker drugs (carvedilol) or variceal banding. Participants will be on the study for 12 months duration and if randomised to the carvedilol arm, they will be prescribed to take carvedilol 12.5 mg for 12 months daily, and they will be seen in clinic at 4 weeks, at 6 and 12 months to see how they progress. Participants will also be asked to take part in two qualitative interviews so that we understand how they feel about being in the trial. This will be after randomisation and the second one from 6-12 months. If participants are randomised to the variceal band ligation arm, they will have up to 5 endoscopy band ligations over the 12 months, and the number of endoscopy visits will depend on how well the varices are eradicated. Participants will also be asked to take part in two qualitative interviews so that we understand how they feel about being in the trial. This will be after randomisation and the second one from 6-12 months.

What are the possible benefits and risks of participating?
Although there may be no direct benefits to participants for taking part in this study, the results of the trial will lead to the best treatment being offered to prevent bleeding in patients with liver cirrhosis and medium or large oesophageal varices. Variceal banding has been used for nearly 30 years and is generally very safe. As banding is an endoscopic procedure about 1 in 10 patients may experience discomfort and find it difficult to tolerate the procedure. Infrequent complications include bleeding affecting about 1 in 20 patients, and a very small risk of causing narrowing of the gullet making it difficult to swallow or causing a tear in the gullet (perforation). Carvedilol is a medication that was initially developed to treat high blood pressure and some forms of heart disease. As with any drug, there are potential minor side effects that affect around half of patients, but serious complications are very rare. The side effects of carvedilol which can be difficult to tolerate in about 1 in 10 patients include: shortness of breath, low blood pressure causing dizziness, and upset stomach. Other less common side effects include abnormal vision, bradycardia (slow heart rate), asthenia (fatigue), and impotence. We will carefully monitor any side effects and take action where needed. It is important that medium to large varices are treated so if participants are not able to tolerate variceal banding or carvedilol, they will be offered an alternative treatment. All the tests participants will receive and procedures that will be undertaken are part of normal clinical care for patients with oesophageal varices. There will be an independent safety committee that will oversee the trial.

Where is the study run from?
The trial is run from Birmingham Clinical Trials Unit and at least 66 hospitals/ Health boards around the UK will be involved in recruitment.

When is the study starting and how long is it expected to run for?
March 2018 to February 2024

Who is funding the study?
National Institute for Health Research Health Technology Assessment Programme (UK)

Who is the main contact?
Lisa Holden
calibretrial@trials.bham.ac.uk

Study website

https://www.birmingham.ac.uk/calibretrial

Type

Scientific

Contact name

Dr Lisa Holden

ORCID ID

Contact details

Birmingham Clinical Trials Unit (BCTU)
Institute of Applied Health Research
College of Medical and Dental Sciences
Public Health Building
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 7943
l.m.holden@bham.ac.uk

EudraCT/CTIS number

2018-002488-24

IRAS number

ClinicalTrials.gov number

Protocol/serial number

RG_17-229

Scientific title

CArvediloL versus varIceal Band ligation in primary pREvention of variceal bleeding in liver cirrhosis

Acronym

CALIBRE

Study hypothesis

To compare carvedilol versus variceal band ligation in preventing any variceal bleeding within 1 year of randomisation in patients with cirrhosis and medium to large oesophageal varices that have never bled.

Ethics approval(s)

Approved 19/10/2018 NHS HRA North East - York REC, (Priory Street Centre, Priory Street, York, YO1 6ET; 0207 104 8079; nrescommittee.northeast-york@nhs.net), ref: 18/NE/0296.
CTA MHRA approval granted 20/09/2018.

Study design

Interventional prospective multicentre pragmatic open-label two-arm randomised controlled parallel group trial with internal pilot

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

https://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/portfolio-v/CALIBRE/investigators/documentation.aspx

Condition

Variceal bleeding in liver cirrhosis

Intervention

After participant eligibility has been confirmed and informed consent has been received, the participant can be randomised into the trial. A Randomisation Form will be provided to investigators and will be used to collate the necessary information prior to randomisation. All questions and data items on the Randomisation Form must be answered before a Trial Number can be given. If data items are missing, randomisation will be stopped, but can be restarted once the information is available. Only when all eligibility criteria and baseline data items have been provided will a Trial Number be allocated. Participants will be randomised at the level of the individual in a 1:1 ratio to either treatment with 12.5 mg carvedilol once daily for 12 months or variceal band ligation. Both of these treatments will start on the same day as randomisation, or as soon as possible after. Patients randomised in clinic after the diagnostic endoscopy will be started on carvedilol 12.5 mg once daily for 12 months or variceal band ligation within two weeks of randomisation. A minimisation algorithm will be used within the online randomisation system to ensure balance in the treatment allocation over the following variables: presence or absence of hepatic decompensation (ascites or encephalopathy), size of the largest varix (Grade II, or Grade III), age of patient at randomisation (18-50, 51-70, >70), and presence or absence of alcohol related liver disease. A ‘random element’ will be included in the minimisation algorithm, so that each patient has a probability (unspecified here), of being randomised to the opposite treatment that they would have otherwise received. Full details of the randomisation specification will be stored in a confidential document at BCTU.
Participants will be in the study for a total duration of 12 months from the point of randomisation.

Intervention type

Drug

Pharmaceutical study type(s)

Phase

Phase III

Drug/device/biological/vaccine name(s)

Carvedilol

Primary outcome measure

Any variceal bleeding within 12 months of randomisation, assessed through endoscopy for the variceal band ligation (VBL) and through observation for the carvedilol arm at 4 weeks and after 6 and 12 months

Secondary outcome measures

1. Time to first variceal bleed in days from randomisation, assessed through endoscopy for the variceal band ligation (VBL) and through observation for the carvedilol arm at 4 weeks and after 6 and 12 months
2. Mortality at 12 months from randomisation, assessed using medical records and staff notification after 6 and 12 months:
2.1. All-cause mortality
2.2. Liver-related mortality
2.3. Cardiovascular mortality
3. Transplant-free survival at 12 months after randomisation, assessed using medical records and staff notification after 6 and 12 months
4. Adverse events related to treatment up to 12 months after randomisation, assessed using follow-up case report forms (CRFs), medical records and staff notification after 6 and 12 months:
4.1. Dysphagia
4.2. Symptomatic hypotension
4.3. Dyspnoea
4.4. Gastrointestinal upset
5. Other complications of cirrhosis, assessed using follow-up case report forms (CRFs), medical records and staff notification after 6 and 12 months:
5.1. New onset ascites
5.2. New onset encephalopathy
5.3. Spontaneous bacterial peritonitis
5.4. Hepatocellular carcinoma
5.5. Any renal dysfunction
6. Health-related quality of life, assessed using the EQ-5D-5L at the baseline and after 6 and 12 months
7. Use of healthcare resources, cost and cost-effectiveness, based on:
7.1. Cost per variceal bleeding avoided within 12 months of randomisation, assessed using a follow-up CRF
7.2. Cost per Quality-Adjusted Life Year (QALY) estimated using the EQ-5D-5L
7.3. Cost per death avoided at 12 months, assessed using a follow-up CRF
8. Patient preferences, assessed using qualitative interviews that explore patients' experience of and preferences related to treatment (carvedilol or VBL), providing the basis to describe qualitatively patients' experience of the trial interventions. The first interview will be just after randomisation (ideally wuthin 2 weeks) and the second will be 6-12 months after randomisation.
9. Use of alternative therapies, assessed using a follow-up CRF after 6 and 12 months
10. Crossover therapies, assessed using a follow-up CRF after 6 and 12 months

Overall study start date

01/03/2018

Overall study end date

29/02/2024

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Liver cirrhosis as defined clinically, radiologically (USS and transient elastography), or on histology
2. Medium varices (Grade II varices that do not flatten on air insufflation and do not occlude the lumen) and large varices (Grade III varices which are larger than Grade II varices and occupy the whole lumen) that have never bled as defined in the BSG guidelines
3. Aged 18 years or older

Participant type(s)

Patient

Age group

Adult

Lower age limit

18 Years

Sex

Both

Target number of participants

2630

Total final enrolment

266

Participant exclusion criteria

Current exclusion criteria as of 24/11/2021:
1. Age <18 years
2. Pregnant or lactating women
3. Known intolerance or contraindications to beta-blockers including asthma
4. Current or past history of non-selective beta-blocker use (such as carvedilol, nadolol or propranolol)
5. Current or history of variceal band ligation
6. Presence of malignancy or systemic disease that significantly affects 1-year survival
7. Unable to give informed consent
8. Diagnosed with acute alcoholic hepatitis at the point of randomisation
9. Patients with surgical or radiological portosystemic shunts such as transjugular portosystemic stent-shunt (TIPSS)
10. Previous organ transplantation

Previous exclusion criteria:
1. Pregnant or lactating women
2. Known allergy to carvedilol
3. Already on non-selective beta-blockers that could not be discontinued
4. Presence of malignancy or systemic disease that significantly affects 1-year survival
5. Unable to give informed consent
6. Contraindications to beta-blockers including asthma
7. Acute alcoholic hepatitis

Recruitment start date

22/01/2019

Recruitment end date

31/08/2022

Countries of recruitment

England, Northern Ireland, Scotland, United Kingdom, Wales

Study participating centre

Basildon and Thurrock University Hospital NHS Foundation Trust
Nethermayne
Basildon
SS16 5NL
United Kingdom

Study participating centre

Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Study participating centre

University Hospital Coventry & Warwickshire NHS Trust
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Study participating centre

County Durham and Darlington NHS Foundation Trust
University Hospital of North Durham
North Road
Durham
DH1 5TW
United Kingdom

Study participating centre

The Newcastle upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital
Newcastle
NE7 7DN
United Kingdom

Study participating centre

Gateshead Health NHS Foundation Trust
Queen Elizabeth Hospital
Sheriff Hill
Gateshead
NE9 6SX
United Kingdom

Study participating centre

Greater Glasgow and Clyde Health Board
GI Offices
4th Floor Walton Building
Glasgow Royal Infirmary
Castle Street
Glasgow
G4 0SF
United Kingdom

Study participating centre

Gloucestershire Hospitals NHS Foundation
Department of Hepatology
Orchard Centre
Gloucestershire Royal Hospital
Gloucester
GL1 3NN
United Kingdom

Study participating centre

Hull University Teaching Hospitals
Gastroenterology and Hepatology Research Department
Level 8 Alderson House
Hull Royal Infirmary
Anlaby Road
Hull
HU3 2JZ
United Kingdom

Study participating centre

Imperial College Healthcare NHS Trust
Hepatology Clinical Research Facility
Liver & Anti-Viral Unit
Imperial College Healthcare NHS Trust
10th Floor
QEQM
St Mary's
South Wharf Road
London
W2 1NY
United Kingdom

Study participating centre

King's College Hospital
Denmark Hill
Brixton
London
SE5 9RS
United Kingdom

Study participating centre

University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

Study participating centre

The Royal Wolverhampton Trust
New Cross Hospital
Wolverhampton
WV10 0QP
United Kingdom

Study participating centre

NHS Tayside
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom

Study participating centre

Nottingham University Hospitals NHS Trust
Queen's Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom

Study participating centre

Portsmouth Hospitals NHS Trust
Queen Alexandra Hospital
Portsmouth
PO6 3LY
United Kingdom

Study participating centre

Royal Devon and Exeter NHS Foundation Trust
Department of Gastroenterology and Hepatology
Barrack Road
Exeter
EX2 5DW
United Kingdom

Study participating centre

Royal Free London
Institute of Liver and Digestive Health
Upper Third Floor
UCL Medical School Royal Free Campus
London
NW3 2PF
United Kingdom

Study participating centre

York Teaching Hospital NHS Foundation Trust
Scarborough Hospital
Woodlands Drive
Scarborough
YO12 6QL
United Kingdom

Study participating centre

South Tyneside District Hospital
Harton Lane
South Shields
NE34 0PL
United Kingdom

Study participating centre

York Teaching Hospital NHS Foundation Trust
York Hospital
Wigginton Road
York
YO31 8HE
United Kingdom

Study participating centre

Birmingham Heartlands Hospital
Bordesley Green E
Birmingham
B9 5SS
United Kingdom

Study participating centre

University Hospitals Birmingham
Liver Unit
Mindelsohn Way
Edgbaston
Birmingham
B15 2TH
United Kingdom

Study participating centre

NHS Lothian
Liver Unit
Royal Infirmary of Edinburgh
Little France
Edinburgh
EH6 4SA
United Kingdom

Study participating centre

Leeds Teaching Hospitals NHS Trust
Merville Building
St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Study participating centre

Aintree University Hospital NHS Foundation Trust
Lower Lane
Liverpool
L9 7AL
United Kingdom

Study participating centre

Belfast HSC Trust
Liver Unit
1st Floor
East Wing
Royal Victoria Hospital
Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Study participating centre

Greater Glasgow & Clyde Health Board
Administration Block 2nd Floor
Queen Elizabeth University Hospital
1345 Govan Road
Glasgow
G51 4TF
United Kingdom

Study participating centre

NHS Grampian
Aberdeen Royal Infirmary
Aberdeen
AB25 2ZN
United Kingdom

Study participating centre

Royal Liverpool and Broadgreen University Hospitals NHS Trust
Link 5Z
Prescot Street
Liverpool
L7 8XP
United Kingdom

Study participating centre

University Hospital Southampton NHS Foundation Trust
Tremona Road
Southampton
SO16 6YD
United Kingdom

Study participating centre

Cwm Taf University Health Board
Singleton Hospital
Sketty Lane
Swansea
SA2 8QA
United Kingdom

Study participating centre

The Mid Yorks NHS Trust
Pinderfields Hospital
Aberford Road
Wakefield
WF1 4DG
United Kingdom

Study participating centre

Cambridge University Hospitals NHS Foundation Trust
Liver Unit
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Study participating centre

South Tees Hospital NHS Foundation Trust
Endoscopy Centre
James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Study participating centre

University Hospitals Plymouth NHS Trust
Derriford Hospital
Crownhill Road
Plymouth
PL6 8DH
United Kingdom

Study participating centre

Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital
Headley Way
Oxford
OX3 9DU
United Kingdom

Study participating centre

University Hospitals of Derby and Burton NHS Foundation Trust
Royal Derby Hospital
Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Study participating centre

Cardiff and Vale University Health Board
Department of Gastroenterology and Hepatology
Ward A7
University Hospital of Wales
Health Park
Cardiff
CF14 4XN
United Kingdom

Study participating centre

Torbay and South Devon NHS Foundation Trust
Torbay Hospital
Lowes Bridge
Torquay
TQ2 7AA
United Kingdom

Study participating centre

Royal Cornwall Hospital Trust
Department of Gastroenterology and Hepatology
Royal Cornwall Hospital
Treliske
Truro
TR1 3LJ
United Kingdom

Study participating centre

Barts Health NHS Trust
Hepatology Clinical research
Grahame Hayton Unit
Ambose King Centre
Royal London Hospital
Whitechapel Road
London
E1 1BB
United Kingdom

Study participating centre

Sandwell & West Birmingham Hospital NHS Trust
Dudley Road
Birmingham
B18 7QH
United Kingdom

Study participating centre

Sheffield Teaching Hospitals NHS Foundation Trust
Robert Hadfield Level 2
Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom

Study participating centre

North Bristol NHS Trust
Southmead Hospital
Bristol
BS10 5NB
United Kingdom

Study participating centre

NHS Fife
Victoria Hospital
Hayfield Road
Kirkcaldy
KY2 5AH
United Kingdom

Study participating centre

St. George’s University Hospitals NHS Foundation Trust
Blackshaw Road
London
SW17 0QT
United Kingdom

Study participating centre

Northumbria Healthcare Trust
North Tyneside Hospital
Rake Lane
South Shields
NE29 8NH
United Kingdom

Study participating centre

South Tyneside and Sunderland NHS Foundation Trust
South Tyneside Hospital
Harton Lane
South Shields
NE34 0PL
United Kingdom

Study participating centre

Wrightington, Wigan and Leigh NHS Foundation Trust
Royal Albert Edward Infirmary
Wigan lane
Wigan
WN1 2NN
United Kingdom

Study participating centre

Shrewsbury and Telford Hospitals NHS Trust
Royal Shrewsbury Hospital
Mytton Oak Road
Shrewsbury
SY3 8XQ
United Kingdom

Study participating centre

Guy’s and St. Thomas NHS Foundation Trust
Guy’s and St. Thomas Hospital
Westminster Bridge Road
London
SE1 7EH
United Kingdom

Study participating centre

Dudley Group of NHS Hospitals Foundation Trust
Russells Hall Hospital
Pensenett Road
Dudley
DY1 2HQ
United Kingdom

Study participating centre

Chelsea and Westminster Hospital Foundation Trust
Chelsea and Westminster Hospital
369 Fulham Road
Chelsea
London
SW10 9NH
United Kingdom

Study participating centre

Hampshire Hospitals NHS Foundation Trust
Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

Study participating centre

The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
The Royal Bournemouth Hospital
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Study participating centre

Cwm Taf Morgannwg University Health Board
Ynysmeurig House
Navigation Park
Abercynon
CF45 4SN
United Kingdom

Study participating centre

Salisbury NHS Foundation Trust
Salisbury District Hospital
Odstock Road
Salisbury
SP2 8BJ
United Kingdom

Study participating centre

South Tyneside and Sunderland NHS Foundation Trust
Kayll Road
Sunderland
SR4 7TP
United Kingdom

Study participating centre

Great Western Hospitals NHS Foundation Trust
Marlborough Road
Swindon
SN3 6BB
United Kingdom

Study participating centre

Walsall Healthcare NHS Trust
Off Moat Road
Walsall
WS2 9PS
United Kingdom

Organisation

University of Birmingham

Sponsor details

University of Birmingham
Research & Governance
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
Birmingham
B15 2TT
England
United Kingdom

Sponsor type

University/education

Website

https://intranet.birmingham.ac.uk/finance/RSS/Research-Support-Group/Research-Governance/index.aspx

ROR

https://ror.org/03angcq70

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Publication and dissemination plan

Regular newsletters will keep collaborators informed of trial progress, and regular meetings will be held to report progress of the trial and to address any problems encountered in the conduct of the trial.
Results of this trial will be submitted for publication in a peer reviewed journal. The manuscript will be prepared by the CI or delegate and authorship will be determined by the trial publication policy. Participants will be informed of the outcome of the trial via a link to a preview of the publication. A lay summary will also be provided via email or posted to participants prior to publication.
Any secondary publications and presentations prepared by Investigators must be reviewed and approved by the TMG. Manuscripts must be submitted to the TMG in a timely fashion and in advance of being submitted for publication, to allow time for review and resolution of any outstanding issues. Authors must acknowledge that the trial was performed with the support of the University of Birmingham. Intellectual property rights will be addressed in the Clinical Study Site Agreement or between Sponsor and site.

Intention to publish date

01/09/2025

Individual participant data (IPD) sharing plan

This trial will include optional consent to allow linkage to patient data available in NHS routine clinical datasets, including primary care data (e.g. Clinical Practice Research Datalink; CPRD, The Health Improvement Network; THIN, QResearch), secondary care data (Hospital Episode Statistics; HES) and mortality data from the Office of National Statistics (ONS) through NHS Digital and other central UK NHS bodies. The consent will also allow access to other new central UK NHS databases that may appear in the future. This will allow us to double check the main outcomes against routine data sources, and extend the follow-up of patients in the trial and collect long-term outcome and health resource usage data without needing further contact with the trial participants. This is important, as it will link a trial of treatments that may become a clinical standard of care to long-term outcomes that are routinely collected in clinical data, but which may not be collected during the period of the trial.

IPD sharing plan summary

Available on request

Study outputs