Metformin for AAA Growth Inhibition, a Randomized Controlled Trial
Phase: PHASE2
Conditions: Abdominal Aortic Aneurysm
Sponsor: Uppsala University Hospital

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20  
 
1(30)  
 
 
Drug Substance  
Metformin  
                                                                        Study Code 
MAAAGI 
  
Eudra CT number  
2018-004289-33  
  
Protocol version number  
1.1 
  
Date  
2019-08-20 
 
  
 
 
Metformin for AAA Growth Inhibition 
A randomized controlled trial 
 MAAAGI-trial 
 
Sponsor and Principal 
Investigator:   
Anders Wanhainen, MD, PhD, Professor, Dept. of Surgical 
Sciences, Vascular Surgery, Uppsala University, Uppsala, 
Sweden  
Senior co-investigator:   
Anders Gottsäter, MD, Professor, Malmö, Sweden 
Coordinating investigator: Jon Unosson, MD, PhD, Uppsala, Sweden 
Investigators:  
Kevin Mani, MD, Professor, Uppsala, Sweden 
Martin Björck, MD, Professor, Uppsala, Sweden  
Dick Wågsäter, MD, Professor, Uppsala, Sweden 
Moncef Zarrouk, MD, PhD, Malmö, Sweden 
Leena Lehti, MD, Malmö, Sweden 
Tomas Hansen, MD, PhD, Uppsala, Sweden 
Björn Sonesson, MD, Associate professor, Malmö, Sweden 
Lars Karlsson, MD, PhD, Gävle, Sweden  
Birgitta Sigvant, MD, PhD, Karlstad, Sweden 
Anders Hellberg, MD, PhD, Västerås, Sweden 
Sverker Svensjö, MD, PhD, Falun, Sweden 
Mari Holsti, MD, PhD, Umeå, Sweden 
Sven-Erik Persson, MD, Umeå, Sweden 
 
 
 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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The following amendment(s) is/are accompanying the protocol:  
1. Date:   
Contact Person (initials):   
2. Date:   
Contact Person (initials):  
 
SIGNATURE PAGE SPONSOR AND INVESTIGATOR   
 
Anders Wanhainen MD, PhD  
Professor and Consultant Vascular Surgeon  
Department of Surgical Sciences, Vascular Surgery  
Uppsala University Hospital  
SE-751 85 Uppsala  
Sweden  
 
  
Signature and date:     ____________________________________         _______________ 
  
  
INVESTIGATOR  
I, the undersigned, have read and understand the protocol and agree that it contains all 
necessary information for conducting the study.   
I agree to conduct the study according to this protocol and according to the ethical principles 
that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical 
Practice and the applicable national laws and regulations.  
 
 
Investigator:               ____________________________________         
  
 
 
Signature and date:    ____________________________________         _______________ 
 
 
 
 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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TABLE OF CONTENTS  
  
TITLE ….……........................................................................................................................... 1  
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 5 
1.  
BACKGROUND, RATIONALE AND OBJECTIVES .................................................. 6 
1.1  
Background ...................................................................................................................... 6 
1.2  
Objectives ........................................................................................................................ 7 
1.2.1 Primary objective .............................................................................................................. 8 
1.2.2 Secondary objectives ......................................................................................................... 8 
1.2.3 Exploratory objectives ....................................................................................................... 8 
1.2.4 Safety objective ................................................................................................................. 8 
2.  
STUDY PLAN AND PROCEDURES ............................................................................ 8 
2.1  
Study design .................................................................................................................... 8 
3.  
PATIENT SELECTION CRITERIA ............................................................................ 11 
3.1  
Inclusion criteria ............................................................................................................ 11 
3.2  
Exclusion criteria ........................................................................................................... 11 
4.  
STUDY CONDUCT ..................................................................................................... 12 
4.1  
Treatment ....................................................................................................................... 12 
4.1.1 Labelling .......................................................................................................................... 13 
4.1.2 Procedures for randomisation .......................................................................................... 13 
4.1.3 Compliance ...................................................................................................................... 14 
4.1.4 Concomitant treatment(s) ................................................................................................ 14 
4.2  
Withdrawal from study .................................................................................................. 15 
5. 
COLLECTION AND RECORDING OF STUDY VARIABLES ................................ 15 
5.1  
Study measurements ...................................................................................................... 15 
5.1.1 Clinical data ..................................................................................................................... 15 
5.1.2 Imaging ............................................................................................................................ 16 
5.1.3 Telephone contacts .......................................................................................................... 17 
5.2  
 Safety ............................................................................................................................ 17 
5.2.1 Definition of adverse events ............................................................................................ 17 
5.2.1 Assessment of intensity ................................................................................................... 17 
5.2.2 Assessment of causality .................................................................................................. 18 
5.2.3 Definitions of serious adverse event ............................................................................... 18 
5.2.4 Recording of adverse events ........................................................................................... 18 
5.2.5 Follow-up of unresolved adverse events ......................................................................... 19 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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5.2.6 Reporting of serious adverse events ................................................................................ 19 
5.2.7 Temporary withdrawal .................................................................................................... 19 
5.2.8 Procedures in case of medical emergency ....................................................................... 19 
5.2.9 Laboratory safety assessment .......................................................................................... 19 
5.3  
Pregnancy ...................................................................................................................... 20 
5.4  
Insurance ........................................................................................................................ 20 
6.  
ETHICAL CONDUCT OF THE STUDY .................................................................... 20 
6.1  
Ethics and regulatory review ......................................................................................... 21 
6.2  
Informed consent ........................................................................................................... 21 
6.3  
Risks – Benefits ............................................................................................................. 22 
7.  
DATA MANAGEMENT .............................................................................................. 23 
7.1  
Monitoring of the study ................................................................................................. 23 
7.2  
Data management .......................................................................................................... 24 
8.  
STATISTICAL METHODS ......................................................................................... 24 
8.1  
Analysis set .................................................................................................................... 24 
8.2  
Outcome variables ......................................................................................................... 25 
8.2.1 Primary variable .............................................................................................................. 25 
8.2.2 Secondary variables ......................................................................................................... 25 
8.2.3 Safety variables ............................................................................................................... 25 
8.3  
Statistical analysis ......................................................................................................... 25 
8.4  
Sample size estimation .................................................................................................. 26 
9.  
CRITERIA FOR TERMINATION OF THE STUDY .................................................. 26 
10.  
INTERIM ANALYSIS .................................................................................................. 27 
11.  
REFERENCES .............................................................................................................. 28 
 
 
 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Study Protocol.  
 
Abbreviation or  
Explanation  
special term  
 
AAA  
Abdominal Aortic Aneurysm  
AE  
Adverse Event  
eCRF  
Electronic Case Report Form  
CT  
Computed Tomography 
DMP  
Data Management Plan  
DVP  
Data Validation Plan 
GFR 
Glomerular Filtration Rate 
ITT  
Intention to Treat  
PPA 
Per Protocol Analysis  
Qol 
Quality of Life 
SmPC 
Summary of Product Characteristics 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US  
Ultrasound  
 
 
 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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1.  
BACKGROUND, RATIONALE AND OBJECTIVES  
1.1  
Background  
Abdominal aortic aneurysm (AAA) is a major health issue and ruptured AAA a common 
cause of death in Europe and North America. In Sweden 700-1000 annual deaths are 
attributed to AAA. To prevent rupture, early detection and preventive surgical repair in 
selected individuals is recommended. AAA screening programs are already implemented in 
the UK, Sweden and the USA. Most screening detected AAAs are, however, small (diameter 
30-54 mm) and are under surveillance until expansion to the threshold for elective surgical 
repair; i.e. diameter ≥55 mm for men and ≥50 mm for women. Presently approximately 
15,000 men and women are being monitored for small AAAs in Sweden, of whom 70% 
eventually will require surgical repair. In 2015, ~1200 AAA repairs were performed in 
Sweden at a cost of ~30 million Euros (Swedvasc 2016). AAA repair is associated with 
significant mortality (1-5%), perioperative complications (up to 20%), cost (~25,000 
Euros/patient) and need for life-long post-operative follow-up, imaging and repeat surgery (in 
~20% of cases) (Mani 2009, Mani 2010, Mani 2013). 
A key limitation of contemporary treatment strategies of AAA is the lack of therapy directed 
at small AAA (Wanhainen 2019). Although surgical repair is an effective treatment for large 
AAA, several large trials (Powell JT 2007, UKSAT 2002, Lederle 2002, Cao 2011) have 
shown that early surgery of small AAA does not reduce mortality. Given that AAA diameter 
is the strongest predictor for rupture and the natural course for AAA is continued expansion, a 
mean to reduce AAA growth rate would be highly beneficial. Commonly used cardiovascular 
drugs, such as anti-platelet drugs, statins, angiotensin converting enzyme inhibitors and beta-
blockers have not been shown to slow AAA growth in cohort studies (Ferguson 2010, Twine 
2011). Previous interventional trials with therapy directed at AAA growth reduction include 
antibiotics, mast cell inhibitors, beta-blockers, platelet inhibitors, and angiotensin converting 
enzyme blockers, with trials of stem cells and cyclosporine under way. These trials have all 
been either small, with negative results or had unacceptable side effects (Meijer 2013, Sillesen 
2015, PATI 2002, Golledge 2017, Rughani 2012). 
Risk factors for AAA often mimic those of arteriosclerosis, with the notable exception of 
diabetes mellitus. Several large trials have shown that people with diabetes are less likely to 
develop AAA and when they do; the AAA expands slower and is less likely to rupture (Xiong 
2016, Kent 2010, Lederle 1997, Golledge 2008, Thomson 2013, De Rango 2012, Takagi 
2016, Theivacumar 2014). However, in 2016 a study of 58 patients with diabetes reported that 
the drug metformin, the world’s most widely used drug for type II diabetes, was associated 
with reduced AAA growth (Fujimura 2016). Following this, a cohort study of 1.2 million 
patients with diabetes, reported that metformin prescription was associated with a 36% 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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reduced risk of developing an AAA (Hsu 2016) and in a cohort of 1755 AAA patients a 36-
76% slower AAA growth rate were reported in patients with diabetes and metformin 
prescription, but not those without (Golledge 2017). A similar finding was made in a cohort of 
13,834 American veterans with AAA and diabetes where metformin was independently 
associated with reduced growth rates of AAA of different sizes (Itoga 2018).  
Metformin may reduce AAA growth by inhibiting key pathological mechanisms implicated in 
AAA, including inflammation and extracellular matrix remodeling. Two different rodent 
models of AAA have found that metformin may reduce AAA growth in euglycemic animals 
(Fujimura 2016, Vasamsetti 2015). These studies suggest that metformin may reduce AAA 
growth by reducing aortic inflammation, elastin degradation, smooth muscle cell depletion 
and monocyte infiltration independent of glucose levels.  
In house data (in manuscript) from a cohort of 526 patents under surveillance for small AAA 
support these findings with a reduced AAA growth rate and altered cytokine expression in 
patients prescribed metformin. In a connected experimental animal study, metformin was also 
shown to inhibit AAA formation, improve endothelial vasomotor function and reduce pro-
inflammatory gene expression in euglycemic mice. 
Metformin is a well-established first-line treatment of type II diabetes. It acts primarily by 
reducing blood glucose levels by inhibiting hepatic glucose production and increase insulin 
sensitivity. It is cheap, safe and able to reduce micro- and macrovascular complications and 
overall death (UKPDS 1998, Holman 2008, Griffin 2017). This has prompted several large 
trials of metformin given to persons without diabetes (DPPRG 2002, Syngelaki 2016) 
showing that metformin is safe and highly tolerable in variable patient groups. 
Metformin is available as a generic drug at low cost. It is generally well tolerated, with few 
serious side effects. Gastro intestinal problems may occur primarily in the run-in phase. This 
is usually mitigated by taking metformin with a meal and increasing the dose stepwise over a 
course of several weeks to the desired level. 
As metformin is a generic drug there is no commercial interest in exploring its potential as a 
drug to reduce AAA growth, necessitating an academically driven trial. 
The rationale for this randomised controlled trial is to investigate whether treatment with 
metformin inhibits growth of small AAAs.   
 
1.2  
Objectives  
The proposed multi-centre population-based open-label randomized controlled trial with 
blinded outcome assessment will examine if metformin slows AAA growth in patients with 
small AAAs who do not have diabetes. 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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1.2.1 Primary objective  
To examine if up to 2g metformin administered daily over a five-year period slows AAA 
growth measured as computed tomography (CT) imaging assessed AAA diameter in patients 
with small AAAs who do not have diabetes.  
An interim STOP/GO analysis will be performed after two-years of treatment.  
 
1.2.2 Secondary objectives  
To examine if metformin limits increase in; a) CT-assessed AAA volume; b) ultrasound 
assessed AAA diameter; c) improves health-related quality of life; d) reduces the need for 
surgery (diameter ≥55mm) or rupture; and e) represents a cost-effective treatment to reduce 
the need for AAA surgery. 
 
1.2.3 Exploratory objectives 
To examine; a) if there is a dose or time related response of metformin regarding the primary 
or secondary endpoints; and b) if metformin favourably modifies circulating inflammation 
and matrix remodelling biomarkers; or c) affects perivascular adipose tissue. 
 
1.2.4 Safety objective  
To determine adverse events; primarily related to known side effects of metformin and 
possible unexpected effects on AAA, related to metformin treatment after two and five years. 
 
2.  
STUDY PLAN AND PROCEDURES  
2.1  
Study design   
The MAAAGI-trial is a population-based multi-center, prospective, parallel group, 
randomized, open label trial with blinded outcome assessment to assess if metformin up to 2g 
daily over a five-year period will reduce AAA growth in patients who do not have diabetes.  
Patients will be recruited from a cohort of patients with diagnosed AAA at the following 
seven Swedish sites; 1) Uppsala University hospital, Uppsala, 2), Skåne University hospital, 
Malmö, 3) Gävle county hospital, Gävle, 4) Västerås county hospital, Västerås. 5) Karlstad 
county hospital, Karlstad 6) Falun county hospital, Falun, and 7) Umeå University Hospital, 
Umeå. 
The patients should have a maximum aortic diameter of 30-49mm for men and 30-44mm for 
women, not have diabetes and be expected to tolerate metformin.   
A total of 500 patients with AAA will be included in the study, 250 in each study arm. 
Patients will be randomised to metformin or standard care in a 1:1 ratio.  

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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The patients are scheduled for one enrolment visit, eight study visits and ten phone contacts 
for those randomized to metformin (three to support titration of study drug) and seven phone 
contacts for those randomized to standard care. The study visits will take place at the vascular 
laboratory at the respective surgical departments for clinical examination and blood sampling 
and at the CT units at the radiology departments where CT-imaging will be performed.  
After a run in phase to support titration of metformin, visits and phone contacts are scheduled 
to alternate every three months until 24 months and twice yearly thereafter. CT imaging and 
AAA US will be performed at baseline, 24 months and end of study, as well as if necessary 
according to clinical routine. Study drug will start at baseline and continue through 
completion.  
End of study is defined as 1) study completion at 60 months, or 2) discontinuation from study 
before that for any reason, for example due to AAA repair or patients will.  
When all patients have completed the 24-month follow-up (including imaging) an interim 
analysis will be performed to assess for efficacy and safety; if there is no trend towards a 
positive effect or signs of a harmful effect of metformin, the study will be stopped at this 
phase. 
The study will be performed in accordance with the ethically acceptable principles that have 
their origin in the Declaration of Helsinki and according to national legislations and 
international regulations. In addition, the study will be performed in accordance with this 
study protocol.   
 
 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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Enrolment 
Baseline/ Visit 1 
Phone 2* 
Phone 3* 
Phone 4* 
Phone 5 
Visit 6 
Phone 7 
Visit 8 
Phone 9 
Visit 10 
Phone 11 
Visit 12 
Phone 13 
Visit 14 
Phone 15 
Visit 16 
Phone 17 
Completion 
Visit window 
 
Day 01 
2 weeks 
4 weeks 
6 weeks 
3 months 
6 months 
9 months 
12 months 
15 months 
18 months 
21 months 
24 months 
30 months 
36 months 
42 months 
48 months 
54 months 
60 months 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In- & exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current medication 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Physical examination3 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Vital signs4 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
QoL questionnaires5 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
CT scan 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Blood samples6 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound7 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Drug prescription* 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
Drug accountability* 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Target dose of study drug* 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
AE registration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAE registration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Table 1. Overview of study activities. Phone 2-5 are to be performed +/- 5 days from target 
date and the remaining activities +/- 4 weeks from target date. 
                                                 
1 Within four weeks of enrollment 
2 Demographics includes date of birth, sex and ethnicity  
3 Physical examination includes cardio-pulmonary status and general appearance  
4 Vital signs include blood pressure, heart rate, height (only at enrollment) and body weight  
5 EQ-5D and RAND-36 
6 Safety lab at all sites and blood samples for biobank at Uppsala and Malmö 
7 Final Ultrasound +/- one week from CT scan 
* For those randomized to metformin only, see item 4.1.1 below 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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3.  
PATIENT SELECTION CRITERIA  
Patients under surveillance for small AAA are identified through local registers at respective 
site. Those with the most recently examined AAA are screened for eligibility. All patients 
scheduled for enrolment visit are accounted for. 
 
3.1  
Inclusion criteria  
For inclusion in the study patients should fulfil the following criteria:  
1. 
Provision of written informed consent.   
2. 
Male and female patients.   
3. 
Age 50-80 years.  
4. 
Documented AAA Ø 30-49 mm for men and 30-44 mm for women. 
5. 
Fasting p-glucose <7.0 mmol/L (WHO 1999). Fasting is defined as no caloric 
intake for ≥8 h. 
 
3.2  
Exclusion criteria  
Patients should not enter the study if any of the following exclusion criteria are fulfilled:  
1. 
Short expected survival.   
2. 
History of current or previous diabetes mellitus. 
3. 
Current or previous use of metformin. 
4. 
Not expected to tolerate metformin. 
5. 
Contraindications to metformin treatment according to SmPC:  
a 
Renal failure with glomerular filtration rate (GFR) <45ml/min according to 
the revised Lund-Malmö formula.  
b 
Hypersensitivity to metformin or any of the excipients included in the tablet. 
c 
Acute metabolic acidosis. 
d 
Diabetic pre-coma. 
e 
Acute conditions with the potential to alter renal function such as; 
dehydration, severe infection or shock 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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f 
Acute or chronic disease which may cause tissue hypoxia such as; 
decompensated heart failure, respiratory failure, recent myocardial infarction 
or shock 
g 
Hepatic insufficiency, acute alcohol intoxication, alcoholism 
6. 
Known or suspected connective tissue disorder (Marfans syndrome, etc), infected 
or inflammatory aneurysm, aneurysm development after aortic dissection or 
previous surgery of the infrarenal aorta.   
7. 
Enrolment in either another investigational drug or medical device study or another 
investigational study of an approved drug or medical device within 30 days prior to 
enrolment of the current study.  
8. 
If, in the opinion of the investigator, it is not in the patient’s medical interest to 
participate in the study or the patient is unlikely to be able to comply with the study 
protocol.  
9. 
Pregnancy. Women of childbearing potential are only included after a confirmed 
menstrual period and a negative highly sensitive urine or serum pregnancy test as 
well as willingness to comply with highly effective anti-contraception throughout 
the study period, see 5.3.  
 
4.  
STUDY CONDUCT  
4.1  
Treatment  
The treatment allocation in this study will consist of;  
• 
Study Arm 1; Metformin tablets taken orally with target dose of 2g daily 
• 
Study Arm 2; Standard care as described in current AAA guidelines (Wanhainen 2019)  
Standard care includes help with smoking cessation if applicable; encouragement of physical 
activity and a healthy diet; blood pressure control; statin and anti-platelet therapy treatment if 
the patient have clinical manifestations of atherosclerotic disease. Local guidelines dictate 
which classes of drugs are recommended and who is responsible for treatment and follow up. 
The study participants allocated to metformin receive standard care plus metformin treatment.    
Patients will be encouraged to take metformin every day at similar times, preferably with a 
meal to minimize side effects.  
Metformin is titrated stepwise to avoid gastrointestinal side effects. Starting dose is one tablet 
of metformin 500mg day 1-14, two tablets day 15-28, three tablets day 29-42 and four tablets 
daily from day 43 till the remainder of the study. If a patient misses one dose he/she is 

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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encouraged to take one extra tablet with the following dose. No more than one dose should be 
compensated for if missed.  
If a patient has severe side effects in the run-in phase, titration to target dose will be slowed. If 
a patient has severe side effects at the target dose, the target dose will be reduced to a level at 
which the side effects are tolerable and stay at this level for the remainder of the study. Target 
dose and compliance to this dose is recorded at each contact.  
 
Table 2. Identity of investigational product(s)  
Investigational product  
Dosage form and strength  
Study arm and time point 
Metformin 
Tablet 500mg, 1 daily 
Study arm 1, Day 0-14 
Metformin 
Tablet 500mg, 2 daily 
Study arm 1, Day 15-28 
Metformin 
Tablet 500mg, 3 daily 
Study arm 1, Day 29-42 
Metformin 
Tablet 500mg, 4 daily 
Study arm 1, Day 43-completion 
 
Target dose of metformin 2g is chosen to reflect doses given in observational studies. It is 
predicted to be a sufficient dose to translate to a meaningful biologic effect whilst still safe 
and with acceptable side effects. The option to reduce the dose is expected to reduce drop-out 
rate. Once the final target dose is reached a different metformin tablet strength may be used 
for convenience, i e 1g rather than 500mg tablets. 
 
4.1.1 Labelling  
The study medication will be prescribed by the investigator and retrieved by the patient at the 
pharmacy. The prescription note will state that the drug is used for study purpose. The patients 
are being reimbursed for their study drug costs. 
 
4.1.2 Procedures for randomisation  
On signing the Informed Consent the patients will be enrolled (enrolment = the process of 
allocating a unique identifier to a patient on entry into a clinical study, after obtaining written 
Informed Consent) and identified with a unique enrolment code (E-code) of 4 digits where the 
first digit is the site number and the three following the patient number. Uppsala=1, Malmö=2, 
Gävle=3, Västerås=4, Karlstad=5, Falun=6, and Umeå=7.  

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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Enrolment will take place before treatment randomisation (randomisation = the assignment of 
patients to treatment in a clinical study according to a randomisation schedule generated by a 
random process) to assure allocation concealment. A randomisation list will be generated 
using a computerized procedure, by sorting 275 treatment allocations in each arm in random 
order using Excel (Microsoft, WA, USA). A total of 550 treatment allocations will be 
generated to accommodate possible erroneous entries to the database. Patients will be 
randomised strictly sequentially as they are eligible for randomisation. Simple randomization 
will be used without stratification given the large number of subjects.    
The patients will be randomized on a 1:1 schedule to; metformin tablets in incremental doses 
to 2g daily or standard care.  
If a patient discontinues from the study, the patient number will not be reused, and the patient 
will not be allowed to re-enter the study.  
 
4.1.3 Compliance 
The patient is asked to note missed doses of medicine for any reason. The patient brings used 
bottles of metformin and receipts from the pharmacy at the study visit and remaining doses 
are counted to calculate compliance. Three consecutive days or more of missed medication are 
noted separately.  
 
4.1.4 Concomitant treatment(s)  
Medication, which is considered necessary for the patient’s safety and well-being, may be 
given at the discretion of the investigator(s).   
All medication is allowed, except for antidiabetic agents. If the need for antidiabetic 
medication should arise, the patient is discontinued from the study.  
The study protocol includes patient history and measures of cardiovascular function such as 
blood pressure, heart rate and cardiac and respiratory auscultation. If un- or undertreated 
diseases or risk factors are discovered, treatment will be initiated as appropriate or the patient 
is referred to relevant care. Active smokers are encouraged to smoking cessation. 
It is likely that CT imaging will generate accidental findings in some patients. These findings 
will be dealt with according to clinical praxis at respective site. It is the responsibility of the 
investigator at respective site to make sure relevant care is provided for patients with 
accidental findings on imaging, laboratory tests or physical examination. 
Concomitant medications will be recorded in the medication list in the eCRF.   
  

Clinical Study Protocol   
Drug Substance Metformin   
Study Code MAAAGI 
Edition Number 1.1 
Date 2019-08-20 
 
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4.2  
Withdrawal from study  
Patients may be discontinued from the study at any time, at the discretion of the investigator.  
Patients are free to discontinue their participation in the study at any time for any reason.  
Patients who discontinue from the study should always be asked about the reason(s) for the 
discontinuation (and informed about their right not to disclose their reason for doing so) and 
the presence of any adverse events (AEs). If possible, they should always be seen and 
assessed by an investigator and asked to perform completion outcome measures, including 
CT, US and QoL questionnaires. A pre-operative CT may be used for follow up should 
indication to operate the aorta arise. Adverse events should be followed up.  
Study treatment should be stopped in the following cases: development of diabetes, persistent 
renal failure with GFR<45ml/min, severely deteriorating health, aortic surgery or onset of 
exclusion criteria. 
If the study medication is stopped, patients will be asked to remain in the study and follow the 
other procedures according to the protocol. All randomised patients remain in the group they 
were originally allocated to for the purpose of intention-to-treat (ITT) analyses.  
Patients who discontinue the study will not be replaced.   
Sponsor has to be informed if a patient is withdrawn by any reason before study end. The 
“End of study” form must be filled out by the investigator and the reason should be stated.  
The study number will not be reused if a patient is withdrawn.   
 
5. 
COLLECTION AND RECORDING OF STUDY VARIABLES  
The patients must sign informed consent before any study specific investigations are 
performed. The investigator will ensure that all data collected in the study, are recorded in a 
timely manner according to any instructions provided. Electronic Case Report Forms (eCRF) 
will be used in this study (See Section 7.2).  
  
5.1  
Study measurements  
5.1.1 Clinical data  
At the enrolment visit the patients will undergo a clinical examination which consists of; 
recording of demographic data (date of birth, sex and ethnicity), medical history and 
concomitant diseases, smoking status, heredity of AAA, current medication, recording of 
weight & height, heart rate & blood pressure, cardio-pulmonary status and general 
appearance.   

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At all points of contact with phone or visit at the clinic any AE and SAE are recorded, target 
dose of study drug is determined and compliance is asked for. Discontinuation (temporarily or 
permanent) of study medication ≥ 3 consecutive days will be recorded.  
At visits medical events and any changes in smoking status will be noted and vital signs and 
weight is recorded. Compliance to study drug is noted and remaining tablets are counted. At 
completion visit and at 24 months, the above plus a physical examination is performed. 
Changes in current medication are recorded yearly. 
At enrolment visit, at 24 months and completion quality of life will be recorded with EQ-5D 
and RAND -36, see appendix 1. 
At enrolment blood samples will be taken for fP-Glc and P-Creatinine, analysed at accredited 
hospital laboratory. P-Creatinine will be tested for safety every 12 months. A 24 months S-
B12 is controlled for possible metformin induced deficiency. In Uppsala and Malmö venous 
blood samples will be taken at baseline, 24 months and completion for scientific reasons. 
 
5.1.2 Imaging  
At baseline, 24 months and completion, the aorta will be examined by non-contrast enhanced 
CT with 1 mm slices or thinner from the jugulum to the groins.  
At enrolment, 24 months and completion the abdominal aorta will be examined by US. The 
assessment of abdominal aortic diameter with US will be done by the local US technician, 
using the standardized technique measuring the largest anterior-posterior diameter from 
leading edge to leading edge perpendicular to the blood flow in the aneurysm. Inclusion 
criteria will be based on US determined diameter.  
If a subject withdraws from the study due to operative need of the aorta, the preoperative CT 
will be used for analysis in the study. The assessment of aortic diameter on CT will be done 
using outer edge to outer edge perpendicular to blood flow. Volumetric AAA analysis of CT 
images will be performed using manual drawing of the vessel wall contours in axial slices of 
the entire abdominal aortic as well as semiautomatic measures in 3mensio, Pie Medical, 
Maastricht. Analysis will start at the slice just below the most distal renal artery excluding 
accessory renal arteries and end at the slice just above the aortic bifurcation. Measures of 
perivascular adipose tissue will be made adjacent to the aorta. 
All CT assessment (diameter and volume) will be done at a core lab at the Department of 
Radiology, Uppsala university hospital, Uppsala. The CT identification is the four digits 
enrolment code. The reviewer will be blinded regarding treatment allocation.  

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CT images will also be reviewed by local radiologists according to GCP at respective hospital. 
Accidental findings of unrelated pathology on the CT scan will be dealt with as appropriate by 
investigator at respective site.  
 
5.1.3 Telephone contacts  
The patients allocated to metformin will initially be contacted by the study nurse every two 
weeks in the run in phase. Thereafter phone contacts are every six months the first two years 
and yearly thereafter. The purpose for these calls is to support the patients in the run in phase 
for those allocated to metformin treatment, record drug accountability and if any AE or SAE 
had occurred since last visit and if previous AE or SAE are resolved.   
 
5.2  
 Safety  
A Summary of product characteristics (SmPC) including safety data of the study drug is 
stored at respective site in the investigators brochure.  
 
5.2.1 Definition of adverse events   
An AE is any unwanted medical occurrence that does not necessarily have to have a causal 
relationship with the investigational product. An AE can be any unfavourable, unintended 
clinical sign, symptom, medical complaint or clinically relevant change in laboratory variables 
or clinical tests. Accidents, operations not pre-planned or deterioration in concurrent illness 
are also considered as AEs. Known gastrointestinal side-effects of metformin are actively 
asked for and noted separately.  
 
5.2.1 Assessment of intensity  
The Investigator should rate the intensity of any AE as follows:  
Mild:           The AE does not interfere with the patient’s usual function.  
Moderate:   The AE interferes to some extent with the patient’s usual function.  
Severe:  
The AE interferes significantly with the patient’s usual function.  
When an AE occurs, the information must be recorded at the AE page. Every AE must be 
followed up and at study end if the AE still occurs, note in the e-CRF, AE outcome – not 
resolved.   
 

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5.2.2 Assessment of causality  
The investigator shall judge whether, in his/her opinion; the AE is potentially associated with 
the study drug. When stating the causality, the following nomenclature should be used: 
Unrelated:  
There is little or no chance that the study treatment   
caused the AE.  
Possibly related:  
The association of the AE with the study treatment is unknown, 
however, the AE is not clearly due to another condition.  
Probably related:  
A reasonable temporal association exists between the AE and the 
study treatment. Based on the Investigator’s clinical experience, the 
association of the AE with the study treatment seems likely.  
5.2.3 Definitions of serious adverse event  
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout or follow-up), that fulfils one or more of the following criteria:  
• 
Results in death  
• 
Is immediately life-threatening  
• 
Requires in-patient hospitalization or prolongation of existing hospitalization   
• 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions  
• 
Is a congenital abnormality or birth defect  
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above  
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s). 
 
5.2.4 Recording of adverse events  
AE + SAE will continuously be recorded from enrolment at all points of contact thru to 
completion at 24 months and documented in the eCRF and AE and SAE log.  
 

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5.2.5 Follow-up of unresolved adverse events  
For all AEs, the patient will be followed until either the AE has ceased or until the patient is 
under professional medical care and a potential causality between the study treatment and the 
AE has been assessed.  
 
5.2.6 Reporting of serious adverse events   
All SAEs will be documented. The investigator is responsible for informing the Regional 
Ethical Review Board, and/or the Regulatory Authority of the SAE as per local requirements.  
The Sponsor is responsible for SAEs reporting to the authorities and SUSARS (Suspected 
Unexpected Serious Adverse Events) reporting. A SUSAR will be reported to authorities if 
the SAE is assessed by the Sponsor to be a SUSAR, i.e. the event is related to the study drug 
and not described in the product specification. The CIOMS form will be used with assistance 
from the Swedish medical products agency. 
A yearly safety report is submitted to the regional ethical review board and medical products 
agency. 
 
5.2.7 Temporary withdrawal 
The patient will be informed to temporarily withdraw the study drug 48h following intra 
venous contrast media injection, in case of vomiting, diarrhoea, fever, reduced fluid intake or 
suspect or manifest dehydration or lactic acidosis according to clinical routine for metformin 
treatment. The study drug is continued following resolution of the risk for dehydration and/or 
temporary renal impairment. See table 2 
 
5.2.8 Procedures in case of medical emergency  
The Investigators should ensure that there are procedures and expertise available to cope with 
emergencies during the study. If an emergency occurs, please notify the Sponsor:  
Name: Anders Wanhainen  
  
Telephone number: 018-6114623, 073-3993906  
 
5.2.9 Laboratory safety assessment  
At enrolment and every 12 months P-Creatinine will be analysed. Metformin may induce 
vitamin B12 deficiency after prolonged treatment and S-B12 is therefore assessed at 24 
months. The blood volume will not exceed 40 mL at each visit, including concurrent blood 
samples for scientific reasons. Extra blood panels will be drawn at the discretion of the 

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investigator if there is concern for primarily renal or hepatic impairment due to alterations in 
clinical status or medication. Elevated fP-Glucose or P-Creatinine discovered at inclusion visit 
or throughout the study will be dealt with according to clinical praxis. Typically by referral to 
the patients family doctor.  
The analyses will be performed at the local hospital laboratories and follow the Swedish 
biobank law for collecting blood samples in a clinical study. Tubes will be labelled and 
handled according to local routines and will be discarded after analysis.  
Blood samples will be taken for scientific reasons in Uppsala and Malmö. Samples are 
centrifuged, frozen and stored for subsequent analysis in accordance with the Swedish 
biobank law for collecting blood samples in a clinical study.  
 
5.3  
Pregnancy  
A limited amount of data from the use of metformin in pregnant women does not indicate an 
increased risk of congenital abnormalities. Risks concerning pregnancy within the study are 
chiefly due to radiation exposure from repeat CT scans. Study participants which are women 
of childbearing potential are required to use birth control methods that can achieve a failure 
rate of less than 1% per year when used consistently and correctly. This includes; combined 
(estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomised partner and sexual abstinence. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. After enrolment into the study, pregnancy 
test for women with childbearing potential will be performed at clinical suspicion only. In 
case of pregnancy the study participant will be withdrawn from the study and, if possible, be 
seen and assessed by an investigator and asked to perform completion outcome measures 
except CT scan due to radiation exposure. 
 
5.4  
Insurance 
All patients in the trial are covered by the patient insurance according to the Patient Injury 
Act.  
    
6.  
ETHICAL CONDUCT OF THE STUDY  
The study will be conducted in accordance with the protocol, applicable regulatory 
requirements, GCP and the ethical principles of the Declaration of Helsinki as adopted by the 
18th World Medical Assembly in Helsinki, Finland, in 1964 and subsequent versions.   

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6.1  
Ethics and regulatory review  
It is the responsibility of the Sponsor to obtain approval of the study protocol/protocol 
amendments, the patient information and the Informed Consent from the ethical review board 
and regulatory authority before enrolment of any patient into the study.   
The written approval from the ethical review board should be dated and have an attached list 
of those persons (with names and positions) present at the meeting.  
The Sponsor shall report all serious and unexpected AEs to the ethical review board. If a study 
stops prematurely at a study centre for any reason, the ethical review board must be informed. 
At the end of the study, the Sponsor should notify the ethical review board.   
The Sponsor should file all correspondence with the ethical review board.  
  
6.2  
Informed consent  
It is the responsibility of the investigator to provide each patient with full and adequate verbal 
and written information about the objectives, procedures and possible risks and benefits of the 
study. All patients should be given the opportunity to ask questions about the study and should 
be given sufficient time to decide whether to participate in the study. The written patient 
information must not be changed without prior discussion with the Sponsor.  
The patients will be notified of their voluntary participation and of their freedom to withdraw 
from the study at any time and without giving any reason. Patients must also be informed that 
withdrawing from the study will not affect their future medical care, treatment or benefits to 
which the patient is otherwise entitled.   
The Investigator is responsible for obtaining written Informed Consent from all patients prior 
to enrolment in the study.   
The patients will consent to:  
- 
Participating in the study.  
- 
Personnel concerned at regulatory authorities to gain full access to hospital records, 
to control the data collected in the study.   
- 
Recording, collection and processing of data and storing of data in a database.  
- 
Collection of blood for analysis and storage in a biobank. 
- 
Possible transfer of information from the study to countries outside the European 
Union (EU).   

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It should be clearly stated that the data will not identify any patient taking part in the study, in 
accordance with the EU General Data Protection Regulation (GDPR).  
A copy of the patient information and the Informed Consent form should be given to the 
patient. The Investigator (or the designated representative) who gave the verbal and written 
information to the patient shall sign the Informed Consent form. The Investigator should file 
the signed Informed Consent forms in the Investigator’s File for possible future audits and 
inspections.   
It is suitable to notify the patient’s family doctor of the patient’s consent to participate in the 
study.   
  
6.3  
Risks – Benefits  
The uncertain knowledge state supporting the study-hypothesis emphasizes the importance of 
a risk assessment for each patient. A risk determination of potential risks in this study has 
been made. These risks together with the actions to minimize these risks are compiled below:  
 
RISKS 
ACTION 
Suspected drug related adverse 
event, such as gastrointestinal 
events 
If not tolerated, treatment with study drug should be 
reduced in dose or stopped, temporarily or permanent, and 
appropriate medical action should be initiated according to 
the nature and severity of the AE. 
Patient require surgery or 
intravenous contrast media during 
study 
Temporary discontinuation of the study drug according to 
clinical praxis for metformin. Typically 48 h after 
intravenous contrast media, in the perioperative phase and 
during fasting. 
Patient develops suspect or 
manifest dehydration during study 
If risk of dehydration for any reason the study drug is 
temporarily discontinued. This typically includes but is 
not limited to fever, serious infection, vomiting, diarrhoea 
and reduced fluid intake. 
Patient develops suspect or 
manifest hypoxia during study 
If risk of hypoxia for any reason the study drug is 
temporarily discontinued. This typically includes but is 
not limited to, sepsis, chock, myocardial infarction and 
decompensated heart failure. 

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Patient requiring continuous 
treatment with drugs that may 
temporarily affect renal function, 
such as NSAIDs 
Study drug should be discontinued during treatment if 
there is evidence of renal impairment 
Patient develops B12 deficiency 
secondary to metformin treatment 
S-B12 levels are controlled every 24 months and 
replacement therapy is initiated if indicated 
BENEFITS 
Other than obtaining an extensive medical evaluation and close monitoring of the AAA, no 
clear benefit was identified for the patients who participate in the study. 
Table 2, possible risks and planned action 
 
7.  
DATA MANAGEMENT  
All data management will be handled by the investigator(s).  
 
7.1  
Monitoring of the study  
In accordance with the principles of Good Clinical Practice (ICH GCP), monitoring of the 
study will be arranged by the Sponsor/PI. Three research nurses with formal training in 
monitoring according to ICH-GCP will monitor the study. During the study, the Monitor will 
have regular contacts with the study sites, including visits to ensure that the study is conducted 
and documented properly in compliance with the protocol, GCP and applicable regulatory 
requirements.   
The extent of monitoring is described in a monitoring plan. The Monitor will ensure that 
accountability of investigational products is performed and will review source documents for 
verification of consistency with the data recorded in the eCRFs. The Monitor will also provide 
information and support to the investigators. The monitor will have access to all data in the 
eCRF, whereas investigators at each site only have access to data from their own site. The PI 
may access the data at all time. 
Questionnaires, lab data, medical records and consent forms are source data stored in the 
investigator file as well as data entered directly in the eCRF and imaging. 
The study centre may also be patent to quality assurance audit by the authorities. The 
investigators and other responsible personnel must be available during the monitoring visits 
and inspections and should devote sufficient time to these processes.   

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The investigators should provide curriculum vitae (CV) to be responsible for the study, as well 
as all personnel at the delegation list. All investigators and other responsible personnel should 
be listed together with their function in the study on the signature and delegation list.   
  
7.2  
Data management  
Anonymised clinical data will be entered in an eCRF created in RedCap, provided by Uppsala 
University.  
The investigator is responsible for ensuring the accuracy, completeness and timeliness of the 
data recorded in the eCRFs. The monitor will check the accuracy and completeness of the data 
reported in the eCRF’s on a regular basis and before the database is locked.   
The eCRF will be in accordance with the study specific Data Validation Plan (DVP). All 
inconsistencies detected during this procedure will be resolved through queries being issued to 
the investigational site. Any corrections made to entered data will be audited.  
Data entered to the eCRF will be anonymised. Records of which e-code each patient is 
allocated will be kept locally at each site in a secure location. 
All imagining will be reviewed anonymised by an operator blinded to treatment allocation. 
  
8.  
STATISTICAL METHODS  
All statistical analyses will be performed by the investigator(s).  
 
8.1  
Analysis set  
All patients for whom a signed informed consent was obtained and an eCRF was started will 
be accounted for.  
The Safety Analysis Set will include all patients who received at least one dose of study drug.  
An intention-to-treat (ITT) analysis will include all randomised patients who received at least 
one dose of study drug and for whom at least one post dose observation for an efficacy 
endpoint is recorded.  
The per-protocol analysis (PPA) consists of patients who sufficiently complied with the 
protocol. Inclusion in the PPA will require at least the following:  
• 
An at least 80% compliance with the intended use will be accepted as per protocol.  
• 
No major protocol deviations.  

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• 
Measure of primary efficacy endpoint at 60 months after baseline, and at 24 months 
for the interim analysis.  
All efficacy analyses will be performed as both ITT and PPA. The ITT analyses is to be 
considered as main and the PPA as supportive.  
 
8.2  
Outcome variables  
8.2.1 Primary variable  
Efficacy in this study will be assessed by difference of AAA diameter determined by CT after 
24 and 60 months vs at baseline, expressed as mm/year. The primary outcome is effect on 
AAA growth rate following 60 months metformin treatment vs standard care. 
 
8.2.2 Secondary variables  
Secondary efficacy variables are; 1) difference in log-transformed AAA-volume determined 
by CT at 24 and 60 months vs at baseline (Log-transformation is undertaken because AAA 
volumes appear to follow a right-skewed distribution based on in house data), 2) difference in 
AAA-diameter determined by US at 24 and 60 months vs at baseline, 3) difference in 
circulating inflammation and matrix remodelling biomarkers assessed by established assays, 
4) difference in quality of life score at 24 and 60 months vs at baseline, 5) difference in need 
for AAA surgery and aneurysm rupture at 24 and 60 months and 6) cost effectiveness of 
metformin treatment 2 g daily to reduce need for prophylactic surgery of AAA. 
 
8.2.3 Safety variables  
Safety variables include differences in drug related AE and GFR.  
  
8.3  
Statistical analysis  
The primary efficacy end-point is the between groups difference in mean annual AAA growth 
over 60 months. AAA growth will be analysed using an analysis of covariance (ANCOVA) 
model where AAA growth at 60 months is the dependent variable and treatment group and 
baseline AAA is included as independent variables. The results will be presented as the 
estimated group difference with 95 % confidence intervals at 60 months.  
Similar methods will be used to assess growth as log transformed CT-volume and ultrasound 
diameter. Analysis of other outcomes: 1) Laboratory data and perivascular adipose tissue are 
exploratory endpoints and will be reported with descriptive statistics and evaluated with 
appropriate inferential statistics, 2) Patient reported outcome (QoL questionnaires) will be 
analysed using non-parametric test (Wilcoxson rank-sum test), 3) Pre-defined clinical events, 

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such as AAA-repair, rupture and death, are expected to be few, and the presentations will use 
descriptive statistics, 4) Economic analysis: Will be performed adopting a health system 
perspective. The cost-effectiveness analysis will produce an incremental cost effectiveness 
ratio as an estimated cost per surgical procedure avoided. 
Handling of missing values: The primary analyses will be performed among patients with a 
measured value at the specific time point. However, as the number of missing values might be 
substantial several sensitivity analyses of the primary analysis will be performed: 
• 
Multiple imputation (with different assumptions)  
- Assume that drop-outs respond according to randomized group 
- Assume that drop-outs respond according to control group 
• 
Fixed imputation depending on reason for drop-out 
- For clinical events, such as AAA-repair, rupture and death, impute worst possible 
value.  
- For other events impute using a maximum likelihood function 
 
8.4  
Sample size estimation   
Based on in house data and original data from an Australian study of the relationship between 
metformin and AAA growth (Golledge 2017) it is conservatively estimated that metformin 
treatment will lead to a 30% reduction in annual AAA growth. This is regarded as a 
meaningful change which is likely to translate to an important reduction in requirement for 
AAA repair. MRI data from the Uppsala group show a mean growth rate of 3mm/year, SD 
2.17. Thus needing 184 patients for 80% power at a 30% reduced growth rate. CT data will 
likely show 10-15% larger SD, adding a 30% dropout rate over five years we approximate a 
need to recruit 500 patients, 250 in each arm, for 80% power at 2-tailed α 0.05. 
  
9.  
CRITERIA FOR TERMINATION OF THE STUDY  
The Sponsor reserves the right to discontinue the study prior to inclusion of the intended 
number of subjects but intends to exercise this right only for valid scientific or administrative 
reasons. After such a decision, all delivered unused investigational products and other study 
related materials must be collected without delay and all eCRFs must be completed as far as 
possible.  
 
 

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The study could be prematurely discontinued in the following cases (examples):  
• 
Unexpectedly high proportion of drug related AEs.  
• 
New findings about the investigational product(s) that changes the benefit/risk ratio.  
• 
Study protocol is difficult to cope with.  
• 
Recruitment of eligible subjects is far too low.  
• 
Unacceptable low investigator or subject compliance.  
• 
Critical change in personnel, administrative or scientific standards at the at the study 
centre.  
 
 10.  
INTERIM ANALYSIS 
When all patients have completed the 24-month follow up (including imaging), an interim 
analysis will be performed where the primary endpoint, as well as log transformed CT-
volume and ultrasound diameter will be analysed using ANCOVA. If there is no trend 
towards a protective effect (all three p-values for treatment effect >0.2), or a significant 
harmful effect on AAA growth or AAA related events, the study will be terminated and all 
on-going metformin treatment stopped.  
The decision how to proceed with the study following the interim analysis will be at the 
discretion of the sponsor. 
 
 
 

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11.  
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