ISRCTN - ISRCTN98001632: MRI assessment for beta-blockers in portal hypertension

Plain English Summary

Background and study aims
Portal hypertension (PHT) is where the blood pressure in the main vein of the liver (the portal vein) becomes too high. If a person has cirrhosis (irreversible scarring of the liver caused by liver disease), blood flow through the portal vein is disrupted, leading to an increase in blood pressure. This can lead to the smaller veins that supply the portal vein bursting, causing bleeds inside the gullet (varices). Non-selective beta-blockers (NSBB) are a type of medication used to treat various conditions including angina (chest pain) and high blood pressure. Long-term treatment with beta-blockers can help to reduce the risk of varicies, but less than one third of patients respond to these drugs and a fifth stop treatment due to side effects. New drugs are emerging that may be more effective and better tolerated. The aim of this study is to find out whether it is possible to develop an effective noninvasive test to monitor the effect of drugs on portal hypertension.

Who can participate?
Adults with liver cirrhosis, who need NSBB treatment for portal hypertension as part of their standard NHS care

What does the study involve?
Participants due to receive NSBB treatment as part of their normal care are randomly allocated to receive treatment with one of two NSBBs. Those in the first group are treated with propranolol and those in the second group are treated with carvedilol (a newer NSBB that is thought to work in a different way). Before starting their treatment and then four weeks later, participants in both groups undergo an MRI scan (a type of body scan that uses strong magnetic fields and radio waves to produce detailed images of the inside of the body) to assess the severity of their liver diseases. In addition, participants also undergo routine laboratory investigations to assess blood flow and general health.

What are the possible benefits and risks of participating?
There are no direct benefits or risks involved with participating.

Where is the study run from?
Royal Infirmary of Edinburgh (UK)

When is the study starting and how long is it expected to run for?
December 2014 to March 2016

Who is funding the study?
Chief Scientist Office (UK)

Who is the main contact?
Dr Jonathan Fallowfield
Jonathan.Fallowfield@ed.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Jonathan Fallowfield

ORCID ID

http://orcid.org/0000-0002-5741-1471

Contact details

MRC Centre for Inflammation Research
Queens Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 (0)131 242 6655
Jonathan.Fallowfield@ed.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

1.2

Study information

Scientific title

Non-invasive assessment of haemodynamic response to beta-blockers using magnetic resonance imaging in patients with portal hypertension

Acronym

Study hypothesis

The aim of this study is to find out whether it is possible to develop an effective noninvasive test to monitor the effect of drugs on portal hypertension (the major cause of complications and death in liver cirrhosis).

Ethics approval

South East Scotland 02 REC, 29/09/2014, ref: 14/SS/1050

Study design

Single-centre open-label randomised parallel trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Portal hypertension

Intervention

Patients with liver cirrhosis who were about to commence non-selective beta-blocker (NSBB) therapy as part of clinical management of portal hypertension (PHT) are enrolled into the study.

Upon enrolment, information on liver disease aetiology, past medical history, medication and alcohol history, and results of the most recent upper gastrointestinal endoscopy are recorded. Prior to starting NSBB therapy, patients undergo a physical examination and routine laboratory investigations (full blood count, coagulation screen, liver and renal function tests), followed by a baseline research MRI scan (phase-contrast MR angiography, liver and spleen T1 mapping). Liver disease severity is also assessed at baseline according to Model for End Stage Liver Disease (MELD) and Child-Pugh score.

Patients are randomised in a 1:1 ratio to once-daily treatment with carvedilol or modified-release propranolol at an initial dose of 6.25mg or 80mg respectively. Patients’ compliance with medication and adverse event monitoring are assessed at an initial follow-up visit after 1 week of NSBB therapy. Provided that NSBB are tolerated clinically and haemodynamically (resting heart rate (HR) ≥50 beats per minute (b.p.m), systolic blood pressure ≥95 mmHg), the dose is escalated to the clinical target dose of 12.5mg of carvedilol or 160mg of propranolol.

Further treatment compliance and adverse event monitoring takes place by weekly telephone consultations. After 4 weeks, when established on NSBB, the second research MRI scan is performed. An interval of 4 weeks has been chosen as haemodynamic responses to NSBB after chronic use exceed the acute response rate. Consistent with a previous landmark NSBB trial in PHT, treatment is targeted at a resting HR reduction of more than 25% from baseline; this was defined as a clinical haemodynamic response to NSBB (HR responders). Following the study, participants continue taking NSBB and are managed by their existing NHS consultant.

Intervention type

Device

Phase

Drug names

Primary outcome measure

Volumetric blood flow [L/min] in selected blood vessels (proper hepatic artery, portal vein, superior mesenteric artery, superior aorta, inferior aorta, renal arteries and azygous vein) measured by phase-contrast MR angiography at baseline and 4 weeks.

Secondary outcome measures

Correlation between MRI blood flow measurements and liver disease severity (using MELD and Child-Pugh scores) assessed at baseline and at 4 weeks.

Overall trial start date

01/12/2014

Overall trial end date

31/03/2016

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Male or female patients aged 18-80 with liver cirrhosis
2. Portal hypertension in whom commencement of beta-blockers is clinically indicated

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

20

Participant exclusion criteria

1. Contraindication to Beta-Blocker therapy (such as moderate to severe asthma)
2. Contraindication to MRI scan
3. Contraindication to administration of gadolinium-based MRI contrast (including eGFR <30mL/min)
4. Concomitant use of other vasoactive drugs (e.g. nitrates, phosphodiesterase inhibitors)
5. Previous TIPSS insertion
6. Portal vein thrombosis
7. Hepatocellular carcinoma
8. Pregnancy or breastfeeding
9. Inability to obtain informed consent (e.g. refusal/overt hepatic encephalopathy)

Recruitment start date

01/01/2015

Recruitment end date

01/03/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
51 Little France Drive
Edinburgh
EH16 4SA
United Kingdom

Sponsor information

Organisation

University of Edinburgh/ACCORD

Sponsor details

Research Governance & QA Office
The Queen's Medical Research Institute
University of Edinburgh
Edinburgh
EH16 4TJ
United Kingdom

Sponsor type

University/education

Website

http://accord.scot/

Funders

Funder type

Government

Funder name

Chief Scientist Office

Alternative name(s)

CSO

Funding Body Type

government organisation

Funding Body Subtype

government non-federal

Location