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Trial registered on ANZCTR


Registration number
ACTRN12613000155796
Ethics application status
Not yet submitted
Date submitted
5/02/2013
Date registered
8/02/2013
Date last updated
8/02/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of blood vessel reactivity in liver cirrhosis
Scientific title
Assessment of vascular response (forearm blood flow) to angiotensin 1-7 infusion as measured by forearm plethysmography in cirrhosis versus health
Secondary ID [1] 281898 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver cirrhosis 288300 0
Condition category
Condition code
Oral and Gastrointestinal 288643 288643 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 (duration- 4 hours total time required, 2 interventions)
Intervention 1- EndoPAT (Itamar, Israel) study to determine the presence and degree of endothelial dysfunction in cirrhosis versus health using this novel non-invasive device.
The EndoPAT study takes fifteen minutes and is performed when biosensor pads are placed on the index fingers of both hands. The brachial artery of one arm is occluded using a pressure cuff for five minutes. When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as reactive hyperaemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software providing the EndoPAT index.

Intervention 2- Forearm Plethysmography (FP)
The brachial artery of the non-dominant arm will be cannulated for the purpose of the FP study. The cannulation will be done with aseptic technique using a 3 French needle under local anaesthesia (1% lignocaine). The cannula will be attached to a pressure transducer and patency maintained with heparinized saline.
Blood pressure and heart rate will be monitored closely throughout the study in the non-cannulated arm using an automated blood pressure recorder. Forearm Blood Flow (FBF) will be monitored using the strain gauge applied around the widest aspect of the forearm approximately one third of the way between the elbow and the wrist. The strain gauge is then attached to a plethysmograph which measures it’s degree of stretch. During recordings hand circulation will be excluded from study by inflating a small cuff at the wrist to 250mmHg. A second cuff will be placed on the upper arm and inflated to 45mmHg to occlude venous outflow. These measures will ensure that only the isolated forearm circulation will be studied. FBF will be monitored for 30 minutes prior to drug infusion to ensure a stable baseline. A drug infusion pump will be used to deliver accurate amounts of drug to participants. The following protocol will be followed in all participants (cirrhotic and controls);

Drug infusion protocol 1
1) Angiotensin-(1-7) infused intra-arterially for five minutes at each of the following doses over a fifteen minute period ; 100pmol/min, 1,000 pmol/min, 10,000 pmol/min. FBF will be measured in the last 2 minutes of each infusion.
2) 20 minute recovery period.
3) Angiotensin II infused intra-arterially for five minutes at each of the following doses over a fifteen minute period; 3pmol/min, 10pmol/min, 30pmol/min. FBF will be measured in the last 2 minutes of each infusion.
4) 20 minute recovery period.
5) Angiotensin-(1-7) infused intra-arterially for fifteen minutes at 100pmol/min and then continued whilst step 3 repeated
6) 20 minute recovery period.
7) L-NMMA (Nitric oxide synthase inhibitor) infused intra-arterially for fifteen minutes at 4micromol/min and then continued whilst step 1 repeated




Arm 2 (duration-2 hour total time required, 2 interventions)
Cirrhotic patients within a 1 year post liver transplantation period only will be asked back to undergo a comparative(pre and post liver transplantation) EndoPAT study and FP study (limited drug infusion protocol)

Drug infusion protocol 2 (post liver transplant only)
1)Angiotensin-(1-7) infused intra-arterially for five minutes at each of the following doses over a fifteen minute period; 100pmol/min, 1,000 pmol/min, 10,000 pmol/min. FBF will be measured in the last 2 minutes of each infusion.
Intervention code [1] 286466 0
Treatment: Drugs
Intervention code [2] 286467 0
Treatment: Devices
Intervention code [3] 286476 0
Early detection / Screening
Comparator / control treatment
Forearm blood flow at baseline and in response to the administered drugs using the technique forearm plethysmography will be compared between healthy and cirrhotic participants.

At a later stage, Forearm blood flow at baseline and in response to the administered drug using the technique forearm plethysmography will be compared between cirrhotic patients who have undergone the study both pre and post liver transplantation.

EndoPAT index as a measure of endothelial dysfunction will be compared between healthy and cirrhotic participants.
EndoPAT index will later be compared in cirrhotic participants before and after liver transplantation.
Control group
Active

Outcomes
Primary outcome [1] 288799 0
The primary outcome of the study will be changes in FBF (from baseline) per minute during Ang 1-7 infusion in ‘cirrhosis’ vs health as measured by FP.

FBF is measured where a strain gauge applied around the forearm is attached to a plethysmograph to record degree of stretch in the gauge. The rate of change in forearm volume gives an estimation of total forearm blood flow expressed as ml/100ml forearm volume per minute.
Timepoint [1] 288799 0
Concentration respone curve to Ang 1-7 over a fifteen minute infusion period
Secondary outcome [1] 301015 0
The comparison of changes in FBF (from baseline) per minute during Ang 1-7 infusion in ‘cirrhosis’ pre and post liver transplantation.

FBF measured as above.
Timepoint [1] 301015 0
Concentration respone curve to Ang 1-7 over a fifteen minute infusion period.
Secondary outcome [2] 301016 0
The effect of Ang II on FBF in health versus cirrhosis.

FBF measured as above.
Timepoint [2] 301016 0
Concentration respone curve to Ang II over a fifteen minute infusion period.
Secondary outcome [3] 301017 0
The effect of Ang II on FBF in the presence of Ang 1-7 in health versus cirrhosis.

FBF measured as above.
Timepoint [3] 301017 0
Concentration respone curve to Ang II over a fifteen minute infusion period with simultaneous Ang 1-7 continuous infusion.
Secondary outcome [4] 301018 0
The effect of Ang 1-7 on FBF in the presence of L-NMMA in health versus cirrhosis

FBF measured as above.
Timepoint [4] 301018 0
Concentration respone curve to Angiotensin 1-7 over a fifteen minute infusion period with simultaneous L-NMMA continuous infusion.
Secondary outcome [5] 301019 0
EndoPAT index in health versus cirrhosis.
Timepoint [5] 301019 0
EndoPAT index calculated after a 20 minute EndoPAT study including a 5 minute brachial artery occlusion period.
Secondary outcome [6] 301020 0
EndoPAT index in cirrhosis pre-liver transplant versus post-liver transplant
Timepoint [6] 301020 0
EndoPAT index calculated after a 20 minute EndoPAT study including a 5 minute brachial artery occlusion period.

Eligibility
Key inclusion criteria
Liver cirrhosis

Absence of liver disease in healthy control group
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Control group participants will not have evidence (clinical/laboratory) of underlying liver disease.

Use of Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Beta blocker medications.
Cardiovascular disease
Hypertension
Pulmonary disease (other than Hepato-Pulmonary Syndrome)
Renal disease (other than Hepato-Renal Syndrome)
>20g alcohol per day in past 6 months.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
In the first arm both groups undergo all interventions.
In the second arm only the disease group is involved.
Phase
Phase 0
Type of endpoint/s
Efficacy
Statistical methods / analysis
The number of participants (n=16) required for this study is based on statistical analysis (power 0.8, p<0.5; SAS for Windows) of previous studies performed by our group using FP to study human vascular reactivity.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2013
Actual
Date of last participant enrolment
Anticipated
1/05/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 545 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 546 0
The Alfred - Prahran
Recruitment postcode(s) [1] 6285 0
3084 - Heidelberg
Recruitment postcode(s) [2] 6286 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 286691 0
Government body
Name [1] 286691 0
National Health and Medical Research Council (NHMRC)
Country [1] 286691 0
Australia
Primary sponsor type
Hospital
Name
Liver Transplant Unit, Austin Health
Address
145 Studley road,
Heidelberg Vic 3084
Country
Australia
Secondary sponsor category [1] 285460 0
None
Name [1] 285460 0
Address [1] 285460 0
Country [1] 285460 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 288754 0
Alfred HREC
Ethics committee address [1] 288754 0
Comercial road,
Prahran
Vic 3181
Ethics committee country [1] 288754 0
Australia
Date submitted for ethics approval [1] 288754 0
25/02/2013
Approval date [1] 288754 0
Ethics approval number [1] 288754 0
n/a

Summary
Brief summary
The purpose of this project is to improve our understanding of the mechanism by which patients with advanced Liver disease (or cirrhosis) develop common complications related to abnormalities in blood flow. These complications include bleeding from the gut (variceal bleeding), behavioural changes (hepatic encephalopathy) and fluid build-up in the abdomen (ascites). Events such as these have a significant impact on patients affected by cirrhosis leading to a deterioration in their quality of life, frequent hospital admissions and in some cases, death. The mechanism behind this abnormal blood flow that occurs in cirrhosis is so far not fully understood. Recently studies performed by our group on animal blood vessels strongly indicate that these problems arise in cirrhosis due to abnormal responses to a hormone, Angiotensin 1-7 (Ang 1-7). As of yet, studies of human blood vessel reactivity to Ang 1-7 in cirrhosis have not been carried out.
We propose to perform detailed analysis of blood vessel reactivity to Ang 1-7 on approximately 16 Austin and Alfred Health patients using a technique called Forearm Plethysmography (FP). The FP study will involve insertion of a small tube (cannula) into an artery of the forearm through which Ang 1-7 and other agents will be delivered. After drugs to be studied have been administered changes in blood vessel reactivity will be assessed using a specially designed band around the forearm which records and measures changes in it’s size. Half of the patients involved in the study will have cirrhosis and will be listed for Liver transplantation. The other half will be patients not affected by Liver disease (‘the control group’). Patients with cirrhosis will be asked to return for a repeat study after they have undergone liver transplantation.
This study will help us to establish the role of Ang 1-7 in human cirrhosis and may lead the way to further research and the development of available therapies.
Also in this study we will evaluate a novel medical device called EndoPAT. EndoPAT is a non-invasive device used to assess the reactivity of blood vessels by applying sensor pads to the tips of the fingers. It's use has not yet been studied in a cirrhotic population where it has the potential to be used as a screening tool to predict complications of cirrhosis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 37638 0
Prof Peter Angus
Address 37638 0
Liver transplant unit,
Austin Health,
145 Studley road,
Heidelberg, Vic 3084
Country 37638 0
Australia
Phone 37638 0
+61394965353
Fax 37638 0
Email 37638 0
peter.angus@austin.org.au
Contact person for public queries
Name 37639 0
Stephen Casey
Address 37639 0
Liver transplant unit,
Austin Health,
145 Studley road,
Heidelberg, Vic 3084
Country 37639 0
Australia
Phone 37639 0
+61394965353
Fax 37639 0
Email 37639 0
scasey@student.unimelb.edu.au
Contact person for scientific queries
Name 37640 0
Stephen Casey
Address 37640 0
Liver transplant unit,
Austin Health,
145 Studley road,
Heidelberg, Vic 3084
Country 37640 0
Australia
Phone 37640 0
+61394965353
Fax 37640 0
Email 37640 0
scasey@student.unimelb.edu.au

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No Supporting Document Provided



Results publications and other study-related documents

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