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

ISRCTN ISRCTN73887615
DOI https://doi.org/10.1186/ISRCTN73887615
EudraCT/CTIS number 2018-002488-24
Secondary identifying numbers RG_17-229
Submission date
08/10/2018
Registration date
10/10/2018
Last edited
15/12/2022
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Digestive System
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year

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

Contact information

Dr Lisa Holden
Scientific

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

Phone +44 (0)121 414 7943
Email l.m.holden@bham.ac.uk

Study information

Study designInterventional prospective multicentre pragmatic open-label two-arm randomised controlled parallel group trial with internal pilot
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Participant information sheet https://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/portfolio-v/CALIBRE/investigators/documentation.aspx
Scientific titleCArvediloL versus varIceal Band ligation in primary pREvention of variceal bleeding in liver cirrhosis
Study acronymCALIBRE
Study hypothesisTo 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.
ConditionVariceal bleeding in liver cirrhosis
InterventionAfter 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 typeDrug
Pharmaceutical study type(s)
PhasePhase III
Drug / device / biological / vaccine name(s)Carvedilol
Primary outcome measureAny 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 measures1. 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 date01/03/2018
Overall study end date29/02/2024

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants2630
Total final enrolment266
Participant inclusion criteria1. 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 exclusion criteriaCurrent 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 date22/01/2019
Recruitment end date31/08/2022

Locations

Countries of recruitment

  • England
  • Northern Ireland
  • Scotland
  • United Kingdom
  • Wales

Study participating centres

Basildon and Thurrock University Hospital NHS Foundation Trust
Nethermayne
Basildon
SS16 5NL
United Kingdom
Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom
University Hospital Coventry & Warwickshire NHS Trust
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom
County Durham and Darlington NHS Foundation Trust
University Hospital of North Durham
North Road
Durham
DH1 5TW
United Kingdom
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital
Newcastle
NE7 7DN
United Kingdom
Gateshead Health NHS Foundation Trust
Queen Elizabeth Hospital
Sheriff Hill
Gateshead
NE9 6SX
United Kingdom
Greater Glasgow and Clyde Health Board
GI Offices
4th Floor Walton Building
Glasgow Royal Infirmary
Castle Street
Glasgow
G4 0SF
United Kingdom
Gloucestershire Hospitals NHS Foundation
Department of Hepatology
Orchard Centre
Gloucestershire Royal Hospital
Gloucester
GL1 3NN
United Kingdom
Hull University Teaching Hospitals
Gastroenterology and Hepatology Research Department
Level 8 Alderson House
Hull Royal Infirmary
Anlaby Road
Hull
HU3 2JZ
United Kingdom
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
King's College Hospital
Denmark Hill
Brixton
London
SE5 9RS
United Kingdom
University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom
The Royal Wolverhampton Trust
New Cross Hospital
Wolverhampton
WV10 0QP
United Kingdom
NHS Tayside
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
Nottingham University Hospitals NHS Trust
Queen's Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Portsmouth Hospitals NHS Trust
Queen Alexandra Hospital
Portsmouth
PO6 3LY
United Kingdom
Royal Devon and Exeter NHS Foundation Trust
Department of Gastroenterology and Hepatology
Barrack Road
Exeter
EX2 5DW
United Kingdom
Royal Free London
Institute of Liver and Digestive Health
Upper Third Floor
UCL Medical School Royal Free Campus
London
NW3 2PF
United Kingdom
York Teaching Hospital NHS Foundation Trust
Scarborough Hospital
Woodlands Drive
Scarborough
YO12 6QL
United Kingdom
South Tyneside District Hospital
Harton Lane
South Shields
NE34 0PL
United Kingdom
York Teaching Hospital NHS Foundation Trust
York Hospital
Wigginton Road
York
YO31 8HE
United Kingdom
Birmingham Heartlands Hospital
Bordesley Green E
Birmingham
B9 5SS
United Kingdom
University Hospitals Birmingham
Liver Unit
Mindelsohn Way
Edgbaston
Birmingham
B15 2TH
United Kingdom
NHS Lothian
Liver Unit
Royal Infirmary of Edinburgh
Little France
Edinburgh
EH6 4SA
United Kingdom
Leeds Teaching Hospitals NHS Trust
Merville Building
St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Aintree University Hospital NHS Foundation Trust
Lower Lane
Liverpool
L9 7AL
United Kingdom
Belfast HSC Trust
Liver Unit
1st Floor
East Wing
Royal Victoria Hospital
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
Greater Glasgow & Clyde Health Board
Administration Block 2nd Floor
Queen Elizabeth University Hospital
1345 Govan Road
Glasgow
G51 4TF
United Kingdom
NHS Grampian
Aberdeen Royal Infirmary
Aberdeen
AB25 2ZN
United Kingdom
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Link 5Z
Prescot Street
Liverpool
L7 8XP
United Kingdom
University Hospital Southampton NHS Foundation Trust
Tremona Road
Southampton
SO16 6YD
United Kingdom
Cwm Taf University Health Board
Singleton Hospital
Sketty Lane
Swansea
SA2 8QA
United Kingdom
The Mid Yorks NHS Trust
Pinderfields Hospital
Aberford Road
Wakefield
WF1 4DG
United Kingdom
Cambridge University Hospitals NHS Foundation Trust
Liver Unit
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
South Tees Hospital NHS Foundation Trust
Endoscopy Centre
James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom
University Hospitals Plymouth NHS Trust
Derriford Hospital
Crownhill Road
Plymouth
PL6 8DH
United Kingdom
Oxford University Hospitals NHS Foundation Trust
John Radcliffe Hospital
Headley Way
Oxford
OX3 9DU
United Kingdom
University Hospitals of Derby and Burton NHS Foundation Trust
Royal Derby Hospital
Uttoxeter Road
Derby
DE22 3NE
United Kingdom
Cardiff and Vale University Health Board
Department of Gastroenterology and Hepatology
Ward A7
University Hospital of Wales
Health Park
Cardiff
CF14 4XN
United Kingdom
Torbay and South Devon NHS Foundation Trust
Torbay Hospital
Lowes Bridge
Torquay
TQ2 7AA
United Kingdom
Royal Cornwall Hospital Trust
Department of Gastroenterology and Hepatology
Royal Cornwall Hospital
Treliske
Truro
TR1 3LJ
United Kingdom
Barts Health NHS Trust
Hepatology Clinical research
Grahame Hayton Unit
Ambose King Centre
Royal London Hospital
Whitechapel Road
London
E1 1BB
United Kingdom
Sandwell & West Birmingham Hospital NHS Trust
Dudley Road
Birmingham
B18 7QH
United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust
Robert Hadfield Level 2
Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom
North Bristol NHS Trust
Southmead Hospital
Bristol
BS10 5NB
United Kingdom
NHS Fife
Victoria Hospital
Hayfield Road
Kirkcaldy
KY2 5AH
United Kingdom
St. George’s University Hospitals NHS Foundation Trust
Blackshaw Road
London
SW17 0QT
United Kingdom
Northumbria Healthcare Trust
North Tyneside Hospital
Rake Lane
South Shields
NE29 8NH
United Kingdom
South Tyneside and Sunderland NHS Foundation Trust
South Tyneside Hospital
Harton Lane
South Shields
NE34 0PL
United Kingdom
Wrightington, Wigan and Leigh NHS Foundation Trust
Royal Albert Edward Infirmary
Wigan lane
Wigan
WN1 2NN
United Kingdom
Shrewsbury and Telford Hospitals NHS Trust
Royal Shrewsbury Hospital
Mytton Oak Road
Shrewsbury
SY3 8XQ
United Kingdom
Guy’s and St. Thomas NHS Foundation Trust
Guy’s and St. Thomas Hospital
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Dudley Group of NHS Hospitals Foundation Trust
Russells Hall Hospital
Pensenett Road
Dudley
DY1 2HQ
United Kingdom
Chelsea and Westminster Hospital Foundation Trust
Chelsea and Westminster Hospital
369 Fulham Road
Chelsea
London
SW10 9NH
United Kingdom
Hampshire Hospitals NHS Foundation Trust
Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom
The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
The Royal Bournemouth Hospital
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom
Cwm Taf Morgannwg University Health Board
Ynysmeurig House
Navigation Park
Abercynon
CF45 4SN
United Kingdom
Salisbury NHS Foundation Trust
Salisbury District Hospital
Odstock Road
Salisbury
SP2 8BJ
United Kingdom
South Tyneside and Sunderland NHS Foundation Trust
Kayll Road
Sunderland
SR4 7TP
United Kingdom
Great Western Hospitals NHS Foundation Trust
Marlborough Road
Swindon
SN3 6BB
United Kingdom
Walsall Healthcare NHS Trust
Off Moat Road
Walsall
WS2 9PS
United Kingdom

Sponsor information

University of Birmingham
University/education

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

Website https://intranet.birmingham.ac.uk/finance/RSS/Research-Support-Group/Research-Governance/index.aspx
ROR logo "ROR" https://ror.org/03angcq70

Funders

Funder type

Government

Health Technology Assessment Programme
Government organisation / National government
Alternative name(s)
NIHR Health Technology Assessment Programme, HTA
Location
United Kingdom

Results and Publications

Intention to publish date01/09/2025
Individual participant data (IPD) Intention to shareYes
IPD sharing plan summaryAvailable on request
Publication and dissemination planRegular 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.
IPD sharing planThis 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.

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Protocol article protocol 01/04/2019 24/05/2019 Yes No
HRA research summary 28/06/2023 No No

Editorial Notes

15/12/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2022 to 31/08/2022.
2. The overall end date was changed from 31/05/2024 to 29/02/2024.
3. The plain English summary was updated to reflect these changes.
4. The total final enrolment was added.
08/02/2022: Recruitment to this study is no longer paused.
25/11/2021: Contact details updated.
24/11/2021: The following changes were made to the trial record:
1. The exclusion criteria were updated.
2. Hampshire Hospitals NHS Foundation Trust, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Cwm Taf Morgannwg University Health Board, Salisbury NHS Foundation Trust, South Tyneside and Sunderland NHS Foundation Trust, Great Western Hospitals NHS Foundation Trust and Walsall Healthcare NHS Trust were added as trial participating centres.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
24/05/2019: The following changes were made to the trial record:
1. Publication reference added (protocol).
2. Link added to participant information sheet.
3. The recruitment start date was changed from 01/11/2018 to 22/01/2019.
4. The recruitment end date was changed from 31/05/2023 to 31/12/2022.
5. The ethical approval date was added.
6. A trial participating centre was changed from Hull and East Yorkshire Hospitals NHS Trust to Hull University Teaching Hospitals.
7. A trial participating centre was changed from Abertawe Bro Morgannwg University Health Board to Cwm Taf University Health Board.
8. An additional 17 trial participating centres were added.
9. Birmingham Clinical Trials Unit at the University of Birmingham was removed from the trial participating centres (this is the trial coordinating centre).
12/10/2018: Internal review.

Springer Nature