Metformin Therapy in Non-diabetic AAA Patients

Phase 2

Active, not recruiting

• Conditions: Abdominal Aortic Aneurysm
• Interventions: Drug: Placebo Oral Tablet; Drug: Metformin Glucophage 500mg (IR) tablets M90

• Registration Number: NCT03507413
• Lead Sponsor: Medical University of Vienna

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 Timeline

• Study First Submitted: 2018-03-29
• Study First Submitted QC: 2018-04-14
• Study First Posted: 2018-04-25
• Study Start: 2018-09-26
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-27
• Last Update Posted: 2024-03-28
• Primary Completion: 2024-05-01
• Study Completion: 2024-05-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 170

Inclusion Criteria

• Infrarenal AAA of 3-4.9 cm maximum diameter

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
COMPARATIVE DRUG	Placebo Oral Tablet	Placebo matching M90 Oral Tablet treatment twice daily (2-0-2) for 1 year
INVESTIGATIONAL DRUG	Metformin Glucophage 500mg (IR) tablets M90	oral metformin treatment with 2000Mg daily: Glucophage 500mg Tablet (2-0-2) daily for 1 year

Primary Outcome Measures

Name	Time	Method
AAA growth over 12 months in mm	12 months	AAA maximum diameter in CT scan

Secondary Outcome Measures

Name	Time	Method
glucose markers insulin and glucose	12 months	inflammatory cytokines and parameters of neutrophil activation in patient plasma
inflammation markers IL-6	12 months	inflammatory cytokines and parameters of neutrophil activation in patient plasma
neutrophil markers NGAL	12 months	inflammatory cytokines and parameters of neutrophil activation in patient plasma
ineutrophil marker MPO	12 months	inflammatory cytokines and parameters of neutrophil activation in patient plasma
neutrophil marker elastase	12 months	inflammatory cytokines and parameters of neutrophil activation in patient plasma
AAA thrombus	12 months	volume of AAA thrombus

Trial Locations

Locations (1)

Medical University of Vienna, Department of Surgery, Division of Vascular Surgery; 🇦🇹 Vienna, Austria