Condition category
Digestive System
Date applied
08/10/2018
Date assigned
10/10/2018
Last edited
12/10/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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 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 which 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 the around UK will be involved in recruitment.

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

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

Who is the main contact?
Dr Khaled Ahmed
calibretrial@trials.bham.ac.uk
k.ahmed.1@bham.ac.uk


Trial website

www.birmingham.ac.uk/calibretrial

Contact information

Type

Scientific

Primary contact

Dr Khaled Ahmed

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
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 7943
k.ahmed.1@bham.ac.uk

Additional identifiers

EudraCT number

2018-002488-24

ClinicalTrials.gov number

Protocol/serial number

RG_17-229

Study information

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

North East - York, CTA MHRA approval on 20/09/2018, 18/NE/0296, awaiting REC approval

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

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Available at www.birmingham.ac.uk/calibretrial

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

Phase

Phase III

Drug names

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 trial start date

01/03/2018

Overall trial end date

31/05/2024

Reason abandoned (if study stopped)

Eligibility

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

Patient

Age group

Adult

Gender

Both

Target number of participants

2630

Participant 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

01/11/2018

Recruitment end date

31/05/2023

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Birmingham Clinical Trials Unit at the University of Birmingham
Institute of Applied Health Research, College of Medical and Dental Sciences, Public Health Building, University of Birmingham, Edgbaston
Birmingham
B15 2TT
United Kingdom

Trial participating centre

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

Trial participating centre

Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

Hull and East Yorkshire Hospitals NHS Trust
Gastroenterology and Hepatology Research Department Level 8 Alderson House Hull Royal Infirmary Anlaby Road
Hull
HU3 2JZ
United Kingdom

Trial 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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

NHS Tayside
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial 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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

NHS Grampian
Aberdeen Royal Infirmary
Aberdeen
AB25 2ZN
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

Abertawe Bro Morgannwg University Health Board
Singleton Hospital Sketty Lane
Swansea
SA2 8QA
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Sponsor information

Organisation

University of Birmingham

Sponsor details

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

Sponsor type

University/education

Website

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

Funders

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

Federal/National Government

Location

United Kingdom

Results and Publications

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.

IPD sharing statement:
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.

Intention to publish date

01/09/2025

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

12/10/2018: Internal review.