ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618001707257

Ethics application status

Approved

Date submitted

21/09/2018

Date registered

16/10/2018

Date last updated

13/05/2022

Date data sharing statement initially provided

8/01/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

The Metformin Aneurysm Trial

Scientific title

The Metformin Aneurysm Trial

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

MAT

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

Study Design: Parallel group, blinded, placebo-controlled randomized clinical trial.
INTERVENTION - metformin extended release: three 500mg capsules per day (1500mg/day).

Pre-randomisation Run-In Titration (-6-0 weeks): Participants in both arms undergoe a single blinded 6-week pre-randomisation run-in as a part of the screening process.
Week 1 - 2: one 500mg capsule per day (~500mg/day).
Week 3 - 4: two 500mg capsules per day (~1000mg/day).
Week 5 - 6: three 500mg capsules per day (~1500mg/day).

Capsules are consumed together once a day.

After randomisation follow-up (approximately 3.5 years post titration period): participants will continue to take 1500mg/day until the end of the trial which is expected to be around 3.5-years.

Compliance with study treatment will be reviewed by asking participants how regularly they take the study treatment (every day [about 100%], nearly every day [about 80-99%], some days [about 40-79%], a few days [about 10-39%], almost never [about 1-9%] or never [0%]). Participants will also asked at each follow-up how many tablets are remaining.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Study Design: Parallel group, blinded, placebo-controlled randomized clinical trial.
PLACEBO - Inert Cellulose Powder: three 500mg capsules per day (1500mg/day).

Pre-randomisation Run-In Titration (-6-0 weeks): Participants in both arms undergoe a single blinded 6-week pre-randomisation run-in as a part of the screening process.
Week 1 - 2: one 500mg capsule per day (~500mg/day).
Week 3 - 4: two 500mg capsules per day (~1000mg/day).
Week 5 - 6: three 500mg capsules per day (~1500mg/day).

After randomisation follow-up (approximately 3.5 years post titration period): participants will continue to take 1500mg/day until the end of the trial which is expected to be around 3.5-years.

Compliance with study treatment will be reviewed by asking participants how regularly they take the study treatment (every day [about 100%], nearly every day [about 80-99%], some days [about 40-79%], a few days [about 10-39%], almost never [about 1-9%] or never [0%]). Participants will also asked at each follow-up how many tablets are remaining.

Control group

Placebo

Outcomes

Primary outcome [1]

AAA-associated events: including AAA repair and AAA mortality (due to aneurysm rupture). This information will be collected via telephone calls with the patient and medical records.

Timepoint [1]

Follow-up will occur until 616 primary outcome events have been accrued (estimated to require a median of ~3.5 years follow-up)

Secondary outcome [1]

AAA growth assessed by maximum AAA diameter on ultrasound

Timepoint [1]

Baseline, every 12 months and at the end of the study (0, 12, 24, 36, 42-48 months)

Secondary outcome [2]

Health-related quality of life and patient-reported outcome measures based SF-36,

Timepoint [2]

baseline, every 12 months and at the end of the study (0, 12, 24, 36, 42-48 months),

Secondary outcome [3]

The occurance of Major Adverse Cardiovascular Events (MACE): defined as non-fatal myocardial infarction, ischaemic stroke or haemorrhagic stroke, plus cardiovascular death (i.e. sudden death, death due to myocardial infarction, valvular heart disease, cardiomyopathy or primary arrhythmia, or other cardiovascular disease or investigations or procedures related to these presentations). This information will be collected from patient interviews and medical records.

Timepoint [3]

Every 3 months until the end of the study.

Secondary outcome [4]

Health-related quality of life and patient-reported outcome measures based on Aneurysm Dependent Quality of Life (AneurysmDQoL) questionnaire

Timepoint [4]

Baseline and every 12 months and at the end of the study (0, 12, 24, 36, 42-48 months),

Secondary outcome [5]

The requirement for peripheral vascular surgical procedure: defined as lower limb peripheral revascularization (open or endovascular), carotid artery revascularisation, other aneurysm repair and major amputation. Incidence of composite event (i.e. first occurrence of any PAD operation) and total number of events will be examined. This will be collected from patient inteview and medical records.

Timepoint [5]

Every three months

Eligibility

Key inclusion criteria

1) An infrarenal AAA with a diameter of 35mm or greater on imaging with the treating doctor indicating that repair is not planned within the next 12 months.

2) At least 18 years old and provides valid informed consent

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1) Symptomatic, ruptured or infected AAA;

2) Previous abdominal aortic surgery;

3) Contraindications to metformin, including renal impairment (eGFR <45ml/min/1.73m2), severe heart failure (defined as New York Heart Association Class IV) requiring in-patient treatment within the last 12 months or leading to shortness of breath at rest, or previous allergic reaction to metformin;

4) Current indication for metformin (i.e. diabetes defined by HbA1c 6.5% or greater);

5) Involvement in another drug trial;

6) Terminal illness

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)

The trial statistician will generate a sequence of unique codes for every active/placebo drug kit. The drug kit codes will be provided to the approved Investigational Medicinal Product (IMP) manufacturer who will ensure that study drug and placebo packs are labelled appropriately, and that the study team, pharmacy staff, investigators and participants are blinded to treatment allocation.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

A random sequence for study arm allocation will be generated by the trial statistician prior to commencement. Randomisation will be conducted using a secure web-based system, and will be stratified by study centre, gender and AAA diameter (35-38.9, 39-42.9, 43-46.9 and 47mm or greater) on ultrasound. Randomisation will be blocked in a 1:1 ratio.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 3 / Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

All participants who have been randomised will be included in the primary analysis, and will be analysed according to their randomly allocated treatment. Statistical analyses will be conducted according to a detailed pre-specified data analysis plan which will be published separately prior to completion of the trial. A brief account of the statistical methods is included here.

For the primary outcome, time-to-event analysis will be conducted to test our hypothesis that metformin will reduce the primary endpoint. The HR and 95% CI will be calculated using Cox proportional analysis, and event risk will be plotted on a Kaplan-Meier graph. A p-value <0.05 will be considered significant.

The focus of the trial will be on the primary hypothesis, but we will also examine the effect of metformin in a small number of pre-specified subgroups including pre-randomisation age, sex, AAA diameter, smoking history and ischemic heart disease, since these are recognised determinants of the primary endpoint. If the primary outcome is negative, any subgroup analysis will be considered purely hypothesis generating since there is a possibility that any such positive findings could be purely attributable to chance. Secondary outcome analyses involving assessment of the effect of metformin on AAA growth and health-related quality of life will be analysed using linear mixed effects models.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

30/10/2020

Actual

8/02/2021

Date of last participant enrolment

Anticipated

5/02/2024

Actual

Date of last data collection

Anticipated

5/08/2027

Actual

Sample size

Target

1954

Accrual to date

101

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

The Townsville Hospital - Douglas

Recruitment hospital [2]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [3]

Sunshine Coast University Hospital - Birtinya

Recruitment hospital [4]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [5]

The Cairns Clinic - North Cairns

Recruitment hospital [6]

Concord Repatriation Hospital - Concord

Recruitment hospital [7]

Wollongong Hospital - Wollongong

Recruitment hospital [8]

Port Macquarie Base Hospital - Port Macquarie

Recruitment hospital [9]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [10]

The Canberra Hospital - Garran

Recruitment hospital [11]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [12]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [13]

Flinders Medical Centre - Bedford Park

Recruitment hospital [14]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [15]

Royal Perth Hospital - Perth

Recruitment hospital [16]

Royal Hobart Hospital - Hobart

Recruitment hospital [17]

Launceston General Hospital - Launceston

Recruitment hospital [18]

Mater Private Hospital - South Brisbane

Recruitment hospital [19]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [20]

Gold Coast Hospital - Southport

Recruitment hospital [21]

Box Hill Hospital - Box Hill

Recruitment hospital [22]

Royal Prince Alfred Hospital - Camperdown

Recruitment postcode(s) [1]

4814 - Douglas

Recruitment postcode(s) [2]

4029 - Herston

Recruitment postcode(s) [3]

4575 - Birtinya

Recruitment postcode(s) [4]

6009 - Nedlands

Recruitment postcode(s) [5]

4870 - North Cairns

Recruitment postcode(s) [6]

2139 - Concord

Recruitment postcode(s) [7]

2500 - Wollongong

Recruitment postcode(s) [8]

2444 - Port Macquarie

Recruitment postcode(s) [9]

2010 - Darlinghurst

Recruitment postcode(s) [10]

2605 - Garran

Recruitment postcode(s) [11]

5011 - Woodville

Recruitment postcode(s) [12]

5000 - Adelaide

Recruitment postcode(s) [13]

5042 - Bedford Park

Recruitment postcode(s) [14]

6150 - Murdoch

Recruitment postcode(s) [15]

6000 - Perth

Recruitment postcode(s) [16]

7000 - Hobart

Recruitment postcode(s) [17]

7250 - Launceston

Recruitment postcode(s) [18]

4101 - South Brisbane

Recruitment postcode(s) [19]

4102 - Woolloongabba

Recruitment postcode(s) [20]

4215 - Southport

Recruitment postcode(s) [21]

3128 - Box Hill

Recruitment postcode(s) [22]

2050 - Camperdown

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland, Christchurch, Waikato, Otago

Country [2]

United Kingdom

State/province [2]

Leicester

Country [3]

Sweden

State/province [3]

Uppsala

Funding & Sponsors

Funding source category [1]

University

Name [1]

James Cook University

Address [1]

James Cook University, 1 James Cook Drive, Townsville QLD 4811 AUSTRALIA

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Australian & New Zealand Society of Vascular Surgery

Address [2]

250-290 Spring Street, East Melbourne, VIC, 3002

Country [2]

Australia

Funding source category [3]

Charities/Societies/Foundations

Name [3]

Royal Australasian College of Surgery

Address [3]

199 Ward Street, North Adelaide, SA, 5006

Country [3]

Australia

Funding source category [4]

Government body

Name [4]

NHMRC

Address [4]

16 Marcus Clarke St Level 1, Canberra Australian Capital Territory 2601

Country [4]

Australia

Primary sponsor type

University

Name

James Cook University

Address

James Cook University, 1 James Cook Drive, Townsville QLD 4811 AUSTRALIA

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Townsville Hospital & Health Service Human Research Ethics Committee

Ethics committee address [1]

HREC Coordinator, The Townsville Hospital, IMB 52, PO Box 670, Townsville, QLD, 4810

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

23/07/2018

Approval date [1]

18/09/2018

Ethics approval number [1]

HREC/QTHS/43408

Ethics committee name [2]

Tasmanian Health and Medical Human Research Ethics Committee

Ethics committee address [2]

301 Sandy Bay Road
Sandy Bay TAS 7005

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

28/01/2020

Approval date [2]

25/05/2020

Ethics approval number [2]

H0018647

Summary

Brief summary

MAT is a multicentre, randomised, placebo-controlled trial to assess if 1500 mg of metformin per day will reduce Abdominal Aortic Aneurysm (AAA)-related events in patients with small AAAs who do not have diabetes. In order to allow reliable assessment of any beneficial effects of metformin on important AAA outcomes, including repair or AAA mortality, follow-up will occur until 616 primary outcome events have been accrued (estimated to require a median of ~3.5 years follow-up). In order to study 1,954 people with small AAA for ~3.5 years at low cost, MAT is streamlined to minimise extra work on collaborating doctors and hospitals. Only essential data will be collected and entered directly into a database. If it can be reliably demonstrated that metformin reduces the risk of AAA events in people with small AAA who do not have diabetes, then this would be relevant to some tens of millions of people worldwide who are currently receiving no treatment of their AAA. This important international study is being led by the Central Coordinating Centre at the Queensland Research Centre for Peripheral Vascular Disease.

Trial website

https://www.jcu.edu.au/qrcpvd

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Jonathan Golledge

Address

Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811

Country

Australia

Phone

+61 07 44331747

Fax

[email protected]

Contact person for public queries

Name

Rene Jaeggi

Address

Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811

Country

Australia

Phone

+61 07 47815449

Fax

[email protected]

Contact person for scientific queries

Name

Jonathan Golledge

Address

Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811

Country

Australia

Phone

+61 07 44331747

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Individual participant data will not be shared to third parties, in accordance to the study protocol.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
935	Informed consent form			[email protected]

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	Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm.	2021	https://dx.doi.org/10.1186/s13063-021-05915-0
Dimensions AI	Mechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysms	2023	https://doi.org/10.1016/j.jvssci.2023.100102

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

Trial Review

Documents added manually

Documents added automatically