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
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