Metformin Therapy in Non-diabetic AAA Patients

Study Overview
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Brief Summary
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A prospective randomized, double blind, placebo-controlled, safety and efficacy study of metformin as add-on therapy in abdominal aortic aneurysm (AAA) OBJECTIVES Primary Objective To demonstrate treatment efficacy of metformin in AAA in comparison to placebo or active comparator, as measured by growth of the AAA maximum diameter at 12 months Secondary Objectives To asses inflammatory cytokines and parameters of neutrophil activation in AAA in response to metformin treatment by glucose insulin Interleukin-6 markers of neutrophil activation (MPO, elastase, NGAL)

Detailed Description
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DESIGN / PHASE Prospective, single-center, randomized, parallel group, double-blind, placebo controlled, phase IIa study STUDY PLANNED DURATION First patient First visit Year 1 1Q Last patient First visit Year 2 4Q Last patient Last visit Year 3 2Q CENTER(S) COUNTRY(IES) 1 center in 1 country Austria PATIENTS / GROUPS 170 patients in 2 groups 85 patients per group Randomization ratio 1:1 Stratification for hypertension, age, smoking habit, sex INCLUSION CRITERIA Infrarenal AAA of 3.0-4.9 cm maximum diameter EXCLUSION CRITERIA premenopausal female patients with a pregnancy possibility patients with diabetes indication for surgical AAA repair life expectancy <2 years contraindications for metformin, i.e. severely reduced kidney function (eGFR <30 ml/min), liver dysfunction, pancreatitis, alcohol abuse, malnutrition and decompensated heart failure STUDY PERIODS 1-2 year recruitment 1 year treatment 12 month follow-up INVESTIGATIONAL DRUG Metformin: initial dose: 500 mg 1-0-1 target dose: 1000 mg 1-0-1 COMPARATIVE DRUG /CONTROL CONDITION Placebo Initial and target dose: tablets 1-0-1 CONCOMITANT MEDICATION Allowed (standard of care) EFFICACY ENDPOINTS AAA growth (in maximum diameter) over 1 year TOLERABILITY / SAFETY surgery when AAA>5.5 cm for men, > 5 cm for women Metformin Therapy for AAA Department of Surgery, Division of Vascular Surgery Medical University of Vienna, Austria ENDPOINTS adverse drug reactions liver insufficiency sustained reduction of kidney function with glomeral filtration rate <30 mg/dl (upon temporary renal insufficiency, infections, exsiccosis, diarrhea and lactic acidosis, metformin treatment will only be paused) PHARMACOKINETIC / PHARMACODYNAMIC ENDPOINTS glucose insulin Interleukin-6 markers of neutrophil activation (MPO, elastase, NGAL) QUALITY OF LIFE / PHARMACOECONOMIC ENDPOINTS gastrointestinal discomfort (as assessed in the initial drop-out phase for patient exclusion) STATISTICAL METHODOLOGY Primary Endpoint AAA growth at 12 months in mm Null and alternative hypotheses: H0: Metformin does not reduce AAA growth H1: Metformin reduces AAA growth from mean 1.7 to 0.4 mm per year Type-I and -II errors: Significance: 5% Power: 80% 1.7±3.3 mm (mean±SD) without Metformin and 0.4±2.3 mm (mean±SD) with Metformin treatment Sample size calculation 77 per group plus 16 patients drop out Total N= 170 Statistical methodology Main analysis set: per protocol Primary endpoint: analysis of covariance adjusted for baseline AAA diameter Pharmacokinetic endpoints: analysis of covariance adjusted for baseline value. Parametric assumptions will be graphically checked with histograms. In case of non-normal distributions analysis of covariance will be performed after a logarithmic or rank transformation. Safety endpoints will be described by cumulative incidence curves

Official Title
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A Prospective Randomized, Double Blind, Placebo-controlled, Safety and Efficacy Study of Metformin as add-on Therapy in Non-diabetic Patients With Abdominal Aortic Aneurysm (MetAAA Study)

Conditions
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Abdominal Aortic Aneurysm

Intervention / Treatment
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* Drug: Metformin Glucophage 500mg (IR) tablets M90
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Infrarenal AAA of 3-4.9 cm maximum diameter Exclusion Criteria: premenopausal female patients with a pregnancy possibility patients with diabetes indication for surgical AAA repair contraindications for metformin, i.e. severly reduced kidney function (eGFR <30 ml/min), liver dysfunction, pancreatitis, alcohol abusus, malnutrition and decompensated heart failure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective, randomized, double blind, placebo-controlled, safety and efficacy study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: INVESTIGATIONAL DRUG<br>oral metformin treatment with 2000Mg daily: Glucophage 500mg Tablet (2-0-2) daily for 1 year | Drug: Metformin Glucophage 500mg (IR) tablets M90<br>* oral metformin Glucophage treatment 500 mg daily (2-0-2) for 1 year<br>* Other names: Glucophage (Merck);|
| Placebo Comparator: COMPARATIVE DRUG<br>Placebo matching M90 Oral Tablet treatment twice daily (2-0-2) for 1 year | Drug: Placebo Oral Tablet<br>* Placebo Oral Tablet M90 treatment twice daily (2-0-2) for 1 year<br>* Other names: Placebo (Merck);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AAA growth over 12 months in mm | AAA maximum diameter in CT scan | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| inflammation markers IL-6 | inflammatory cytokines and parameters of neutrophil activation in patient plasma | 12 months | 
| glucose markers insulin and glucose | inflammatory cytokines and parameters of neutrophil activation in patient plasma | 12 months | 
| neutrophil markers NGAL | inflammatory cytokines and parameters of neutrophil activation in patient plasma | 12 months | 
| ineutrophil marker MPO | inflammatory cytokines and parameters of neutrophil activation in patient plasma | 12 months | 
| neutrophil marker elastase | inflammatory cytokines and parameters of neutrophil activation in patient plasma | 12 months | 
| AAA thrombus | volume of AAA thrombus | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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placebo, abdominal aortic aneurysm, metformin, non-diabetic