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Trial registered on ANZCTR


Registration number
ACTRN12612001226897
Ethics application status
Approved
Date submitted
7/11/2012
Date registered
20/11/2012
Date last updated
21/04/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Fenofibrate in the Management of Abdominal Aortic Aneurysms
Scientific title
Fenofibrate in the Management of Abdominal Aortic Aneurysms
Secondary ID [1] 281467 0
None
Universal Trial Number (UTN)
U1111-1156-5831
Trial acronym
FAME
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Abdominal Aortic Aneurysm (AAA) 287724 0
Condition category
Condition code
Cardiovascular 288061 288061 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Daily oral administration of 145mg of fenofibrate for four+/-two weeks prior to planned open abdominal aortic aneurysm repair. The time frame, +/- two weeks will be decided on a case by case basis. It will be mainly dependant upon the scheduled date of the participant's repair.
Intervention code [1] 285968 0
Treatment: Drugs
Comparator / control treatment
Placebo. The placebo will be indentical in taste and appearance to fenofibrate but without the active ingredient. The frequency and duration of use will also be indentical to the active drug.
Control group
Placebo

Outcomes
Primary outcome [1] 288268 0
Abdominal aortic aneurysm wall machrophage number. Serial cryostat sections 7uM thick will be cut from each AAA wall sample and stained. All samples will be stained simultaneously using identical reagents and incubation times. Serial frozen sections will be air-dried, fixed in acetone for 10 mins at -20 C, air dried and rehydrated with PBS before being incubated in 3%H202/0.1% sodium azide/PBS to block endogenous peroxidase.
Timepoint [1] 288268 0
End of study
Primary outcome [2] 288269 0
Abdominal aortic aneurysm wall Osteopontin (OPN) concentration. Two techniques will be used to assess OPN.
1. ELISA: Protein will be extracted from individual frozen AAA wall biopsies by homogenising in buffer and centrifuging. Supernatant protein will be quantified by the Bradford technique.
2. Immunohistochemistry: Slides will be incubated in 2% normal goat serum in PBS and endogenous avidin and biotin blocked this will then be followed using other measures to assess OPN levels.
Timepoint [2] 288269 0
End of study
Primary outcome [3] 288270 0
Serum Osteopontin (OPN) concentration. Blood will be collected from patients after an overnight faste. Serum was stored at -80 degrees celcius until later batch assessment of OPN concentrations using ELISA according to manufacturer's instructions and expressed as ng/mL.
Timepoint [3] 288270 0
End of study
Secondary outcome [1] 299734 0
Analysis of other inflammatory cells and matric-metallo proteinases by immunohistochemistry and zymography.
Timepoint [1] 299734 0
End of study
Secondary outcome [2] 299735 0
Analysis of circulating concentration of other abdominal aortic aneurysm bionmarkers, including osteoprotegerin, resistin and D-dimer, also fasting lipids. This will be assessed by ELISA and automated assays.
Timepoint [2] 299735 0
End of study
Secondary outcome [3] 299736 0
Genotype and global expression of genes selected from ongoing biomarker studies. The cox proportional hazard analysis will be used to assess the association of circulating biomarkers with patient outcomes.
Timepoint [3] 299736 0
End of study

Eligibility
Key inclusion criteria
Ability to provide written informed consent
Diagnosis of an asymptomatic abdominal aortic aneurysm which is infrarenal in location and is equal to or greater than 50mm in diameter
Planned elective open repair of infrarenal abdominal aortic aneurysm
High likelihood of medication compliance
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Current use of any fenofibrate or related fibrates
contra-indication to fenofibrate including; liver impairment demonstrated by abnormal liver function tests (greater than or equal to 1.5 times normal upper limit); renal impairment (serum creatinine greater than or equal to 150 micromole); symptomatic gallbladder disease; previous reaction to any lipid modifying medication.
Previous aortic surgery
A Mycotic abdominal aortic aneurysm
A requirement for emergency or urgent open abdominal aortic aneurysm repair
Current enrolment in any other drug trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Trial participants who meet the inclusion/exclusion criteria and provide Informed Consent. FAME Randomisation was achieved through computer generated sequence allocation (NQuery Advisor Ver. 9). Central randomisation was carried out by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation was blocked on a 1:1 ratio using mixed block sizes and stratified by recruitment site. All trial staff, investigators and participants are blinded to the randomisation schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 286231 0
Government body
Name [1] 286231 0
NHMRC
Address [1] 286231 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 286231 0
Australia
Primary sponsor type
University
Name
James Cook University
Address
1 James Cook Drive

Townsville

QLD 4811
Country
Australia
Secondary sponsor category [1] 285078 0
None
Name [1] 285078 0
Address [1] 285078 0
Country [1] 285078 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288298 0
Royal Brisbane and Women's Human Research Ethics Committee
Ethics committee address [1] 288298 0
Human Research Ethics Office
Level 7, Block 7
Royal Brisbane and Women's Hospital
Metro North Health Service District
Cnr Butterfield St and Bowen Bridge Rd
HERSTON, QUEENSLAND AUSTRALIA 4029
Ethics committee country [1] 288298 0
Australia
Date submitted for ethics approval [1] 288298 0
Approval date [1] 288298 0
27/08/2012
Ethics approval number [1] 288298 0
HREC/10/QRBW/421
Ethics committee name [2] 288299 0
University of Queensland Human Research Ethics Committee
Ethics committee address [2] 288299 0
Research & Innovation Division
Cumbrae-Stewart Building (72)
Research Road
University of Queensland, Queensland 4072
Ethics committee country [2] 288299 0
Australia
Date submitted for ethics approval [2] 288299 0
Approval date [2] 288299 0
15/06/2012
Ethics approval number [2] 288299 0
2011000862
Ethics committee name [3] 288359 0
James Cook University
Ethics committee address [3] 288359 0
1 James Cook Drive

Townsville

QLD 4811
Ethics committee country [3] 288359 0
Australia
Date submitted for ethics approval [3] 288359 0
Approval date [3] 288359 0
07/04/2011
Ethics approval number [3] 288359 0
C8
Ethics committee name [4] 288360 0
The Townsville Hospital
Ethics committee address [4] 288360 0
100 Angus Smith Drive Douglas Queensland 4814
Ethics committee country [4] 288360 0
Australia
Date submitted for ethics approval [4] 288360 0
Approval date [4] 288360 0
24/08/2011
Ethics approval number [4] 288360 0
HREC/10/QRBW/421
Ethics committee name [5] 288361 0
Mater Health Services NQ Ltd
Ethics committee address [5] 288361 0
Locked Bag 1000
Qld 4814
Ethics committee country [5] 288361 0
Australia
Date submitted for ethics approval [5] 288361 0
Approval date [5] 288361 0
20/08/2012
Ethics approval number [5] 288361 0
MHS20110101-01

Summary
Brief summary
In a pre-clinical study we examined the effect of oral fenofibrate added to drinking water (approximate dose based on average drinking rates 100mg/kg/d) over a 4 week period on aortic dilatation induced by angiotensin II infusion in apolipoprotein e deficient mice [1]. This model is currently the most commonly used animal model of AAA and has a number of pathological similarities to the human condition but like all animal models of complex diseases cannot be considered to be completely comparable [2]. These studies demonstrated that:
a) Fenofibrate inhibited aortic dilatation: mean suprarenal aortic diameters were 1.51+/-0.13 and 2.10+/-0.14mm in fenofibrate treated and control mice, respectively, n=27, P=0.001;
b) Fenofibrate reduced aortic concentration of osteopontin (OPN): median suprarenal aortic OPN concentrations were 126 and 3198 pg/mg protein in fenofibrate treated and control mice, respectively, n=15, P=0.006;
c) Fenofibrate reduced aortic infiltration by macrophages: median suprarenal aortic CD68 staining areas were 4% (interquartile range 2.5-3.9) and 13% (interquartile range 8.4-20.0) in fenofibrate treated and control mice, respectively, n=10, P<0.01.
We have previously shown that OPN is upregulated in human AAA [3] and marked macrophage infiltration is a consistent feature of human AAA [4]. OPN is a known macrophage chemokine and thus aortic OPN would be expected to promote macrophage influx to the aorta. The ability of fenofibrate to downregulate OPN may be critical in reducing macrophage infiltration (and associated release of proteolytic enzymes) and limiting AAA expansion. Within the mice model the downregulation of OPN and inflammation appeared to occur rapidly. Fenofibrate also raises HDL in some human subjects and high HDL has been associated with protection from AAA [5]. The effect of fenofibrate in the mouse model cannot be explained by HDL mechanisms however since this medication does not increase HDL in apolipoprotein e deficient mice [6]. In humans therefore it is postulated that a short cause of fenofibrate will inhibit AAA OPN expression, associated macrophage based inflammation and possibly also induce other beneficial effects by raising HDL.

FAME is a multi-centre, randomised, double-blind, placebo-controlled clinical trial. Participants will be randomised to receive fenofibrate (145mg once a day for 4+/-2 weeks) or placebo (once a day for 4+/-2 weeks), in a parallel group, double blind design. Randomisation lists will be generated by a statistician and provided to the study centres ensuring both Investigators and participants are blinded to drug assignment.

REFERENCES
1.Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of osteoprotegerin with human abdominal aortic aneurysm progression.Circulation. 2005;111:3119-25.
2. Golledge J, Clancy P, Jamrozik K, Norman PE. Obesity, adipokines, and abdominal aortic aneurysm: Health in Men study. Circulation. 2007;116:2275-9.
3. Golledge J, Muller R, Clancy P, McCann M, Norman PE. Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm. Eur Heart J. 2010 Jun 8.
4. Golledge J, van Bockxmeer F, Jamrozik K, McCann M, Norman PE. Association between serum lipoproteins and abdominal aortic aneurysm. Am J Cardiol. 2010;105:1480-4.
5. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 2006;26:2605-13.
6. Golledge J, Cullen B, Rush C, Moran CS, Secomb E, Wood F, Daugherty A, Campbell JH, Norman PE. Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm. Atherosclerosis. 2010;210:51-6.
Trial website
http://ncre-pad.registry.org.au/clinical-studies
Trial related presentations / publications
NA
Public notes

Contacts
Principal investigator
Name 34890 0
Prof Jonathan Golledge
Address 34890 0
School of Medicine
James Cook University
1 James Cook Drive
Douglas, Queensland 4811
Country 34890 0
Australia
Phone 34890 0
+61 7 4433 1442
Fax 34890 0
+61 7 4433 1401
Email 34890 0
jonathan.golledge@jcu.edu.au
Contact person for public queries
Name 18137 0
Mrs Jenna Pinchbeck
Address 18137 0
The Townsville Hospital
Douglas
Queensland 4810
Country 18137 0
Australia
Phone 18137 0
+61 7 44331419
Fax 18137 0
+61 7 44331401
Email 18137 0
jenna.pinchbeck@jcu.edu.au
Contact person for scientific queries
Name 9065 0
Prof Professor Jonathan Golledge
Address 9065 0
Vascular Biology Unit
James Cook University
James Cook Drive
Townsville, Queensland 4810
Country 9065 0
Australia
Phone 9065 0
+61 (0)7 4781 4730
Fax 9065 0
+61 (0)7 4781 3652
Email 9065 0
jonathan.golledge@jcu.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary