Brief Title
Metformin Therapy in Non-diabetic AAA Patients
Official Title
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)
Brief Summary
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
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
Study Phase
Phase 2/Phase 3
Study Type
Interventional
Primary Outcome
AAA growth over 12 months in mm
Secondary Outcome
inflammation markers IL-6
Condition
Abdominal Aortic Aneurysm
Intervention
Metformin Glucophage 500mg (IR) tablets M90
Study Arms / Comparison Groups
INVESTIGATIONAL DRUG
Description: oral metformin treatment with 2000Mg daily: Glucophage 500mg Tablet (2-0-2) daily for 1 year
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
170
Start Date
September 26, 2018
Completion Date
November 15, 2022
Primary Completion Date
October 15, 2022
Eligibility Criteria
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
Gender
All
Ages
18 Years - 99 Years
Accepts Healthy Volunteers
No
Contacts
Christoph Neumayer, MD, ,
Location Countries
Austria
Location Countries
Austria
Administrative Informations
NCT ID
NCT03507413
Organization ID
1479/2017
Responsible Party
Principal Investigator
Study Sponsor
Medical University of Vienna
Collaborators
Merck Serono GmbH, Germany
Study Sponsor
Christoph Neumayer, MD, Principal Investigator, Medical University of Vienna
Verification Date
August 2022