ANZCTR - Registration

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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]

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)

Condition category

Condition code

Cardiovascular

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]

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]

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]

End of study

Primary outcome [2]

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]

End of study

Primary outcome [3]

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]

End of study

Secondary outcome [1]

Analysis of other inflammatory cells and matric-metallo proteinases by immunohistochemistry and zymography.

Timepoint [1]

End of study

Secondary outcome [2]

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]

End of study

Secondary outcome [3]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/08/2012

Actual

17/08/2012

Date of last participant enrolment

Anticipated

Actual

19/12/2016

Date of last data collection

Anticipated

Actual

16/01/2017

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

James Cook University

Address

1 James Cook Drive

Townsville

QLD 4811

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Brisbane and Women's Human Research Ethics Committee

Ethics committee address [1]

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]

Australia

Date submitted for ethics approval [1]

Approval date [1]

27/08/2012

Ethics approval number [1]

HREC/10/QRBW/421

Ethics committee name [2]

University of Queensland Human Research Ethics Committee

Ethics committee address [2]

Research & Innovation Division
Cumbrae-Stewart Building (72)
Research Road
University of Queensland, Queensland 4072

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

Approval date [2]

15/06/2012

Ethics approval number [2]

2011000862

Ethics committee name [3]

James Cook University

Ethics committee address [3]

1 James Cook Drive

Townsville

QLD 4811

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

Approval date [3]

07/04/2011

Ethics approval number [3]

Ethics committee name [4]

The Townsville Hospital

Ethics committee address [4]

100 Angus Smith Drive Douglas Queensland 4814

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

Approval date [4]

24/08/2011

Ethics approval number [4]

HREC/10/QRBW/421

Ethics committee name [5]

Mater Health Services NQ Ltd

Ethics committee address [5]

Locked Bag 1000
Qld 4814

Ethics committee country [5]

Australia

Date submitted for ethics approval [5]

Approval date [5]

20/08/2012

Ethics approval number [5]

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

Prof Jonathan Golledge

Address

School of Medicine
James Cook University
1 James Cook Drive
Douglas, Queensland 4811

Country

Australia

Phone

+61 7 4433 1442

Fax

+61 7 4433 1401

jonathan.golledge@jcu.edu.au

Contact person for public queries

Name

Jenna Pinchbeck

Address

The Townsville Hospital
Douglas
Queensland 4810

Country

Australia

Phone

+61 7 44331419

Fax

+61 7 44331401

jenna.pinchbeck@jcu.edu.au

Contact person for scientific queries

Name

Professor Jonathan Golledge

Address

Vascular Biology Unit
James Cook University
James Cook Drive
Townsville, Queensland 4810

Country

Australia

Phone

+61 (0)7 4781 4730

Fax

+61 (0)7 4781 3652

jonathan.golledge@jcu.edu.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME): Study protocol for a randomised controlled trial.	2017	https://dx.doi.org/10.1186/s13063-016-1752-z
Embase	A Randomised Controlled Trial Assessing the Effects of Peri-operative Fenofibrate Administration on Abdominal Aortic Aneurysm Pathology: Outcomes From the FAME Trial.	2020	https://dx.doi.org/10.1016/j.ejvs.2020.06.006

N.B. These documents automatically identified may not have been verified by the study sponsor.

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