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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] 295670 0
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) 309026 0
Condition category
Condition code
Cardiovascular 307923 307923 0 0
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] 301987 0
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] 306891 0
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] 306891 0
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] 350041 0
AAA growth assessed by maximum AAA diameter on ultrasound
Timepoint [1] 350041 0
Baseline, every 12 months and at the end of the study (0, 12, 24, 36, 42-48 months)
Secondary outcome [2] 350042 0
Health-related quality of life and patient-reported outcome measures based SF-36,
Timepoint [2] 350042 0
baseline, every 12 months and at the end of the study (0, 12, 24, 36, 42-48 months),
Secondary outcome [3] 350043 0
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] 350043 0
Every 3 months until the end of the study.
Secondary outcome [4] 350077 0
Health-related quality of life and patient-reported outcome measures based on Aneurysm Dependent Quality of Life (AneurysmDQoL) questionnaire
Timepoint [4] 350077 0
Baseline and every 12 months and at the end of the study (0, 12, 24, 36, 42-48 months),
Secondary outcome [5] 396305 0
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] 396305 0
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?
No
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] 13739 0
The Townsville Hospital - Douglas
Recruitment hospital [2] 13740 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 13741 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [4] 13743 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [5] 13744 0
The Cairns Clinic - North Cairns
Recruitment hospital [6] 13747 0
Concord Repatriation Hospital - Concord
Recruitment hospital [7] 13748 0
Wollongong Hospital - Wollongong
Recruitment hospital [8] 13749 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [9] 13750 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [10] 13751 0
The Canberra Hospital - Garran
Recruitment hospital [11] 13752 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [12] 13753 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [13] 13754 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [14] 13755 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [15] 13756 0
Royal Perth Hospital - Perth
Recruitment hospital [16] 13757 0
Royal Hobart Hospital - Hobart
Recruitment hospital [17] 13758 0
Launceston General Hospital - Launceston
Recruitment hospital [18] 13759 0
Mater Private Hospital - South Brisbane
Recruitment hospital [19] 19601 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [20] 19602 0
Gold Coast Hospital - Southport
Recruitment hospital [21] 19603 0
Box Hill Hospital - Box Hill
Recruitment hospital [22] 19604 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 26488 0
4814 - Douglas
Recruitment postcode(s) [2] 26489 0
4029 - Herston
Recruitment postcode(s) [3] 26490 0
4575 - Birtinya
Recruitment postcode(s) [4] 26492 0
6009 - Nedlands
Recruitment postcode(s) [5] 26493 0
4870 - North Cairns
Recruitment postcode(s) [6] 26496 0
2139 - Concord
Recruitment postcode(s) [7] 26497 0
2500 - Wollongong
Recruitment postcode(s) [8] 26498 0
2444 - Port Macquarie
Recruitment postcode(s) [9] 26499 0
2010 - Darlinghurst
Recruitment postcode(s) [10] 26500 0
2605 - Garran
Recruitment postcode(s) [11] 26501 0
5011 - Woodville
Recruitment postcode(s) [12] 26502 0
5000 - Adelaide
Recruitment postcode(s) [13] 26503 0
5042 - Bedford Park
Recruitment postcode(s) [14] 26504 0
6150 - Murdoch
Recruitment postcode(s) [15] 26505 0
6000 - Perth
Recruitment postcode(s) [16] 26506 0
7000 - Hobart
Recruitment postcode(s) [17] 26507 0
7250 - Launceston
Recruitment postcode(s) [18] 26508 0
4101 - South Brisbane
Recruitment postcode(s) [19] 34232 0
4102 - Woolloongabba
Recruitment postcode(s) [20] 34233 0
4215 - Southport
Recruitment postcode(s) [21] 34234 0
3128 - Box Hill
Recruitment postcode(s) [22] 34235 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 21483 0
New Zealand
State/province [1] 21483 0
Auckland, Christchurch, Waikato, Otago
Country [2] 21484 0
United Kingdom
State/province [2] 21484 0
Leicester
Country [3] 21485 0
Sweden
State/province [3] 21485 0
Uppsala

Funding & Sponsors
Funding source category [1] 300252 0
University
Name [1] 300252 0
James Cook University
Country [1] 300252 0
Australia
Funding source category [2] 301568 0
Charities/Societies/Foundations
Name [2] 301568 0
Australian & New Zealand Society of Vascular Surgery
Country [2] 301568 0
Australia
Funding source category [3] 301569 0
Charities/Societies/Foundations
Name [3] 301569 0
Royal Australasian College of Surgery
Country [3] 301569 0
Australia
Funding source category [4] 308734 0
Government body
Name [4] 308734 0
NHMRC
Country [4] 308734 0
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] 299673 0
None
Name [1] 299673 0
Address [1] 299673 0
Country [1] 299673 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301073 0
The Townsville Hospital & Health Service Human Research Ethics Committee
Ethics committee address [1] 301073 0
Ethics committee country [1] 301073 0
Australia
Date submitted for ethics approval [1] 301073 0
23/07/2018
Approval date [1] 301073 0
18/09/2018
Ethics approval number [1] 301073 0
HREC/QTHS/43408
Ethics committee name [2] 308654 0
Tasmanian Health and Medical Human Research Ethics Committee
Ethics committee address [2] 308654 0
Ethics committee country [2] 308654 0
Australia
Date submitted for ethics approval [2] 308654 0
28/01/2020
Approval date [2] 308654 0
25/05/2020
Ethics approval number [2] 308654 0
H0018647

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85790 0
Prof Jonathan Golledge
Address 85790 0
Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811
Country 85790 0
Australia
Phone 85790 0
+61 07 44331747
Fax 85790 0
Email 85790 0
jonathan.golledge@jcu.edu.au
Contact person for public queries
Name 85791 0
Rene Jaeggi
Address 85791 0
Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811
Country 85791 0
Australia
Phone 85791 0
+61 07 47815449
Fax 85791 0
Email 85791 0
rene.jaeggi@jcu.edu.au
Contact person for scientific queries
Name 85792 0
Jonathan Golledge
Address 85792 0
Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811
Country 85792 0
Australia
Phone 85792 0
+61 07 44331747
Fax 85792 0
Email 85792 0
jonathan.golledge@jcu.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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.TypeCitationLinkEmailOther DetailsAttachment
935Informed consent form  QRCPVD@jcu.edu.au



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProtocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm.2021https://dx.doi.org/10.1186/s13063-021-05915-0
Dimensions AIMechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysms2023https://doi.org/10.1016/j.jvssci.2023.100102
N.B. These documents automatically identified may not have been verified by the study sponsor.