E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Small abdominal aortic aneurysm (AAA) under active surveillance; 30-49 mm in diameter for men and 30-44 mm in diameter for women |
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E.1.1.1 | Medical condition in easily understood language |
Small abdominal aortic aneurysm under surveillance where the aneurysm diameter is below threshold for surgical repair and not expected to reach this threshold within 24 months of study start |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000054 |
E.1.2 | Term | Abdominal aortic aneurysm |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate if 2 g metformin daily over 60 months reduce yearly growth rate of small abdominal aortic aneurysms in patients with no history of diabetes At 24 months a Stop/Go interim analysis will be performed for safety and efficacy |
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E.2.2 | Secondary objectives of the trial |
To investigate if metformin 2 g per day is tolerable and safe, affects quality of life, affects biomarkers associated with aortic aneurysms and may represent a cost effective medical treatment in patients with a small abdominal aortic aneurysm and no history diabetes |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion 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. No history of diabetes mellitus and fasting p-glucose <7.0 mmol/L |
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E.4 | Principal 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: Hypersenisitivity 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. 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 10. Any condition or laboratory finding which in the opinion of the Investigator makes the patient unsuitable for inclusion. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To examine if 2 g metformin administered daily over a five-year period slows AAA growth rate in patients with small AAAs who do not have diabetes mellitus measured as computed tomography (CT) imaging assessed AAA diameter. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline versus 24 and 60 months of treatment |
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E.5.2 | Secondary end point(s) |
Secondary outcomes To examine if metformin; a) limits increase in CT-assessed AAA volume; b) ultrasound assessed AAA diameter; c) improve health-related quality of life; d) represent a cost-effective treatment to reduce the need for AAA surgery.
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 treatment.
Exploratory objectives To examine; a) if there is a dose or time related response of metformin regarding the primary or secondary endpoints; b) if metformin favorably modify circulating inflammation and matrix remodeling biomarkers; c) affect perivascular adipose tissue.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline versus 24 and 60 months of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Primary outcome measures are performed by an operator blinded to treatment allocation |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard treatment - best medical care |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |