Metformin Therapy in Non-diabetic AAA Patients

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 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

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