Metformin Therapy in Non-diabetic AAA Patients (MetAAA)

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)

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)

Study Overview

• Status: Active, not recruiting
• Conditions: Abdominal Aortic Aneurysm
• Intervention / Treatment: Drug: Metformin Glucophage 500mg (IR) tablets M90; Drug: Placebo Oral Tablet

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 Type: Interventional
• Enrollment (Estimated): 170
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna, Department of Surgery, Division of Vascular Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Merck Serono GmbH, Germany
• Investigators: Principal Investigator: Christoph Neumayer, MD, Medical University of Vienna; Principal Investigator: Wolf-Hans Eilenberg, MD, PhD, Medical University of Vienna

Publications and helpful links

General Publications

• minimale Endnote Formatierung der Refs im Word Dokument probieren!!!

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2018
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): May 1, 2024

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: April 14, 2018
• First Posted (Actual): April 25, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: placebo; metformin; abdominal aortic aneurysm; non-diabetic
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Aortic Diseases; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 1479/2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No