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)

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

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