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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
15/05/2019
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 [100%], most days [80%], some days [40%] or never [0%]).
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 [100%], most days [80%], some days [40%] or never [0%]).
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
Every 12 months and at the end of the study (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
Every 12 months and at the end of the study (12, 24, 36, 42-48 months),
Secondary outcome [3] 350043 0
The composite occurrence of cardiovascular events (myocardial infarction, stroke, death), mortality from all causes combined, development of diabetes mellitus, combination of first and subsequent occurences of the primary outcome and cancer at all sites (excluding any known to pre-date randomisation and non-melanoma skin cancer) and specifically including lung cancer, bowel cancer, bladder cancer and prostate cancer. This information will be collected via telephone calls with the patient 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
Every 12 months and at the end of the study (12, 24, 36, 42-48 months),
Secondary outcome [5] 350078 0
Health-related quality of life and patient-reported outcome measures based on Aneurysm Symptom Rating Questionnaire (AneurysmSRQ).
Timepoint [5] 350078 0
Every 12 months and at the end of the study (12, 24, 36, 42-48 months),

Eligibility
Key inclusion criteria
1. An infrarenal AAA measuring a maximum diameter of 39-49mm;

2. At least 18 years old and provides valid informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Symptomatic, ruptured or infected AAA

2. Current indication for AAA repair according to the treating physician

3. Previous abdominal aortic surgery

4. Contraindications to metformin, including renal impairment (eGFR <45ml/min/1.73 m2), 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 this medication.

5. Current indication for metformin (i.e. Diabetes defined by HbA1c equal or greater than 6.5%)

6. Involvement in another drug trial

7. Terminal illness

8. Clinical concern from the treating physician that the patient is unsuitable for the tria.

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)
Independent online minimisation randomisation program where allocation will be sent to the study pharmacist who will dispense medication in concealed medication bottles
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Independent online minimisation randomisation program which will ensure equal balance of important determinants of between treatment groups. A random element will be included such that the probability of being allocated that treatment determined by the minimization algorithm is 90%.
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 2
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
Not yet recruiting
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)
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] 13742 0
Gosford Private Hospital - Gosford
Recruitment hospital [5] 13743 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [6] 13744 0
The Cairns Clinic - North Cairns
Recruitment hospital [7] 13745 0
Mater Hospital Pimlico - Pimlico
Recruitment hospital [8] 13746 0
Liverpool Hospital - Liverpool
Recruitment hospital [9] 13747 0
Concord Repatriation Hospital - Concord
Recruitment hospital [10] 13748 0
Wollongong Hospital - Wollongong
Recruitment hospital [11] 13749 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [12] 13750 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [13] 13751 0
The Canberra Hospital - Garran
Recruitment hospital [14] 13752 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [15] 13753 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [16] 13754 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [17] 13755 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [18] 13756 0
Royal Perth Hospital - Perth
Recruitment hospital [19] 13757 0
Royal Hobart Hospital - Hobart
Recruitment hospital [20] 13758 0
Launceston General Hospital - Launceston
Recruitment hospital [21] 13759 0
Mater Private Hospital - South Brisbane
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] 26491 0
2250 - Gosford
Recruitment postcode(s) [5] 26492 0
6009 - Nedlands
Recruitment postcode(s) [6] 26493 0
4870 - North Cairns
Recruitment postcode(s) [7] 26494 0
4810 - Pimlico
Recruitment postcode(s) [8] 26495 0
2170 - Liverpool
Recruitment postcode(s) [9] 26496 0
2139 - Concord
Recruitment postcode(s) [10] 26497 0
2500 - Wollongong
Recruitment postcode(s) [11] 26498 0
2444 - Port Macquarie
Recruitment postcode(s) [12] 26499 0
2010 - Darlinghurst
Recruitment postcode(s) [13] 26500 0
2605 - Garran
Recruitment postcode(s) [14] 26501 0
5011 - Woodville
Recruitment postcode(s) [15] 26502 0
5000 - Adelaide
Recruitment postcode(s) [16] 26503 0
5042 - Bedford Park
Recruitment postcode(s) [17] 26504 0
6150 - Murdoch
Recruitment postcode(s) [18] 26505 0
6000 - Perth
Recruitment postcode(s) [19] 26506 0
7000 - Hobart
Recruitment postcode(s) [20] 26507 0
7250 - Launceston
Recruitment postcode(s) [21] 26508 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 21483 0
New Zealand
State/province [1] 21483 0
Auckland
Country [2] 21484 0
United Kingdom
State/province [2] 21484 0
Bristol
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
Address [1] 300252 0
James Cook University, 1 James Cook Drive, Townsville QLD 4811 AUSTRALIA
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
Address [2] 301568 0
250-290 Spring Street, East Melbourne, VIC, 3002
Country [2] 301568 0
Australia
Funding source category [3] 301569 0
Charities/Societies/Foundations
Name [3] 301569 0
Royal Australasian College of Surgery
Address [3] 301569 0
199 Ward Street, North Adelaide, SA, 5006
Country [3] 301569 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
HREC Coordinator, The Townsville Hospital, IMB 52, PO Box 670, Townsville, QLD, 4810
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

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 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
Mrs Jenna Pinchbeck
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
jenna.pinchbeck@jcu.edu.au
Contact person for scientific queries
Name 85792 0
Prof 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?
Study protocol
Informed consent form
How or where can supporting documents be obtained?
Type [1] 935 0
Informed consent form
Citation [1] 935 0
Link [1] 935 0
Email [1] 935 0
Other [1] 935 0
It is anticipated that the study protocol will be published in a peer review journal.

The participant consent form will be made available on the study website.
Attachment [1] 935 0
Summary results
No Results