Metformin Therapy in Non-diabetic AAA Patients (MetAAA)

Medical University of Vienna

Status and phase

Active, not recruiting

Phase 3

Phase 2

Conditions

Abdominal Aortic Aneurysm

Treatments

Drug: Metformin Glucophage 500mg (IR) tablets M90

Drug: Placebo Oral Tablet

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT03507413

1479/2017

Details and patient eligibility

About

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)

Full description

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

Enrollment

170 estimated patients

Sex

All

Ages

18 to 99 years old

Volunteers

No Healthy Volunteers

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