Evaluation of Metformin Embonate on Growth Rate Reduction in Small Abdominal Aortic Aneurysms in Non-Diabetic Patients: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether a daily dose of **metformin** 2 g over a period of 60 months can reduce the yearly growth rate of small abdominal aortic aneurysms (AAA) in patients without a history of diabetes. This is clinically relevant as reducing the growth rate of AAAs could potentially decrease the risk of aneurysm rupture, which is a life-threatening condition. An interim analysis for safety and efficacy will be conducted at 24 months.

Secondary objectives include investigating the tolerability and safety of metformin at this dosage, its impact on quality of life, and its effects on biomarkers associated with aortic aneurysms. Additionally, the study aims to determine if metformin could be a cost-effective treatment option for patients with small AAAs who do not have diabetes.

The clinical trial involves **male and female** participants aged **50-80 years** who are under active surveillance for a **small abdominal aortic aneurysm (AAA)**, with a diameter of 30-49 mm for men and 30-44 mm for women. The study population does not include individuals with a history of diabetes mellitus, and participants must have a fasting plasma glucose level of less than 7.0 mmol/L. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their ability to provide written informed consent and meet the specified age and health criteria. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed to evaluate the efficacy of **metformin embonate** in reducing the growth rate of small abdominal aortic aneurysms (AAA) in patients without a history of diabetes. This is a randomized, controlled, double-blind trial with a primary objective to assess whether a daily dose of 2 grams of metformin over a period of 60 months can slow the growth rate of small AAAs, as measured by computed tomography (CT) imaging. The trial is expected to conclude by January 30, 2026, with recruitment having commenced on February 12, 2020.

Participants will be involved in the study for a total duration of five years, during which they will undergo a series of study visits. The initial visit will serve as a screening to confirm eligibility based on criteria such as age (50-80 years), documented AAA size, and absence of diabetes mellitus. Following the inclusion visit, participants will attend follow-up visits at regular intervals, including assessments at 24 months and 60 months, to monitor the primary and secondary endpoints. These endpoints include changes in AAA diameter and volume, health-related quality of life, and the cost-effectiveness of the treatment. Safety assessments will also be conducted to identify any adverse events related to metformin treatment.

The trial includes a Stop/Go interim analysis at 24 months to evaluate safety and efficacy, which may influence the continuation of the study. Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or if the interim analysis suggests discontinuation. The end-of-study visit will involve a comprehensive evaluation of the treatment's impact on AAA growth and other exploratory objectives, such as the modification of circulating inflammation biomarkers. The trial is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **metformin embonate**, a chemical compound used as the experimental medication. The pharmaceutical form of this medication is designated as PHF00245MIG. The active substance, **metformin embonate**, is also known by its synonyms, metformin hemiembonate and metformin pamoate. The medication is classified under the ATC code A10BA02, which corresponds to the therapeutic category of **metformin**. The route of administration for this trial is oral, with a maximum daily dose of 2000 mg. The treatment period is set for a maximum of 61 months, with the primary objective being to assess the reduction in the yearly growth rate of small abdominal aortic aneurysms in patients without a history of diabetes.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains solely on the administration of the experimental medication, metformin embonate. The trial protocol includes monitoring participant compliance with the dosing schedule to ensure adherence to the prescribed regimen. The study will conduct a Stop/Go interim analysis at 24 months to evaluate safety and efficacy, ensuring that the treatment is both safe and effective for the participants involved.

Efficacy in the clinical trial titled "Metformin for Abdominal Aortic Aneurysm Inhibition (MAAAGI)" will be assessed through a series of primary and secondary endpoints. The primary endpoint is to determine if the administration of 2 g of metformin daily over a five-year period can slow the growth rate of small abdominal aortic aneurysms (AAA) in patients without diabetes mellitus. This will be measured by comparing the **AAA diameter** using computed tomography (CT) imaging at baseline, 24 months, and 60 months of treatment.

Secondary endpoints include evaluating whether metformin limits the increase in CT-assessed AAA volume, ultrasound-assessed AAA diameter, improves health-related quality of life, and represents a cost-effective treatment to reduce the need for AAA surgery. Additionally, safety objectives will focus on determining adverse events, primarily related to known side effects of metformin and any unexpected effects on AAA, assessed after two and five years of treatment. Exploratory objectives will examine if there is a dose or time-related response of metformin regarding the primary or secondary endpoints, and whether metformin favorably modifies circulating inflammation and matrix remodeling biomarkers or affects perivascular adipose tissue.

The efficacy parameters will be collected and analyzed at specified timepoints, including baseline, 24 months, and 60 months, using validated imaging techniques and patient-reported outcomes. The trial will also include a Stop/Go interim analysis for safety and efficacy at 24 months. This structured approach ensures a comprehensive evaluation of metformin's potential benefits in inhibiting the progression of small AAAs in the specified patient population.