The Effects of Metformin on Functional Capacity in Individuals With Peripheral Artery Disease-Related Intermittent Claudication and Abnormal Glucose Metabolism

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Baker IDI Heart and Diabetes Institute
Sponsor:
Information provided by (Responsible Party):
Baker IDI Heart and Diabetes Institute
ClinicalTrials.gov Identifier:
NCT01799057
First received: February 22, 2013
Last updated: November 3, 2013
Last verified: November 2013
  Purpose

The purpose of this study is to determine the effects of metformin on functional capacity (pain-free and maximum walking times) in individuals with peripheral artery disease (PAD)-related intermittent claudication and abnormal glucose metabolism.


Condition Intervention Phase
Peripheral Arterial Disease
Intermittent Claudication
Glucose Metabolism Disorders
Drug: Metformin
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study of Metformin for the Assessment of Changes in Functional Capacity, Endothelial Function, and Hemodynamics in Individuals With Peripheral Artery Disease-Related Intermittent Claudication and Abnormal Glucose Metabolism

Resource links provided by NLM:


Further study details as provided by Baker IDI Heart and Diabetes Institute:

Primary Outcome Measures:
  • Change in pain-free walking time [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
    Pain-free walking time (time to onset of claudication) will be measured during a graded treadmill exercise test.

  • Change in maximum walking time [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
    Maximum walking time will be measured during a graded treadmill exercise test.


Secondary Outcome Measures:
  • Change in questionnaire-based markers of quality of life / perceived functional capacity [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in endothelial function [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in skeletal muscle blood flow response to insulin [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in skeletal muscle blood flow response to acute exercise [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in insulin sensitivity [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in objectively measured physical activity / sedentary behaviour in the daily life setting. [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Change in glucose uptake and insulin signalling mechanisms in skeletal muscle (exploratory endpoint) [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in skeletal muscle oxidative capacity and substrate utilization (exploratory endpoint) [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]
  • Change in inflammation, fibrinolysis and coagulation (exploratory endpoint) [ Time Frame: Measured at baseline and following 16-18 weeks treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: July 2013
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Metformin
Metformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day).
Drug: Metformin
Participants randomized to metformin will be treated at a maximum dose of 2000mg per day (i.e. 1000mg twice daily for 16-18 weeks; up-titrated from 500mg twice daily for the first 2 weeks). Participants may complete the 16-18 week treatment intervention at the lower dose of 500mg twice daily if limited by side effects.
Other Name: Diaformin
Placebo Comparator: Placebo
Matching placebo twice daily for 16-18 weeks.
Drug: Placebo
Participants randomized to placebo will take matching oral capsules according to the same dose schedule specified for the metformin intervention.

Detailed Description:

Background and Rationale:

Metformin has demonstrable efficacy in slowing or reversing the progression of various insulin-resistant disease states - most notably type 2 diabetes and pre-diabetes. In seeking to establish proof-of-concept that insulin resistance is a suitable pathophysiological target in the treatment of PAD-related intermittent claudication (pain in the leg muscles during walking, which resolves on exercise cessation), this study will determine whether the known insulin-sensitizing effects of metformin translate to alleviation of the functional limitations imposed by claudication.

Since type 2 diabetic individuals with PAD often rely on metformin as part of standard risk factor management (glycemic control), the current study will enrol only those with pre-diabetes or non-pharmacologically treated, well-controlled type 2 diabetes. In view of the prevalence of disorders of glucose metabolism in PAD (approximately two-thirds of unselected individuals), this mechanistic study should have far-reaching clinical implications.

Study Design:

A total of 80 individuals with PAD-related intermittent claudication and abnormal glucose metabolism will be randomised (1:1) to either metformin or matching placebo for 16-18 weeks (double-blind, parallel group design). The maximum daily dose of metformin will be 2000mg (up-titrated from half this dose at 2 weeks if tolerated).

Primary Hypothesis:

Improvement in functional capacity follows metformin therapy in individuals with PAD-related intermittent claudication and abnormal glucose metabolism. Change in functional capacity will be assessed by the co-primary endpoints of pain-free and maximum walking times during a standard graded treadmill exercise test.

Secondary Aims:

Exercise testing for functional performance will be complemented by assessments of perceived physical functioning / quality of life in the daily life setting (using standard questionnaires). As previous studies have indicated cardiovascular effects of metformin incremental to blood glucose-lowering, this study will also investigate potential mechanisms of efficacy relating to the primary endpoints, including changes in endothelial function, blood flow responses to various stimuli (including insulin and acute exercise), insulin sensitivity, and physical activity / sedentary behaviours. Changes in relevant clinical data (including ankle-brachial index and limb hemodynamics by duplex scanning) will also be determined.

Outcomes and Significance:

The unmet clinical need of efficacious medical therapies for intermittent claudication is a growing problem given the increasing prevalence of PAD worldwide. If positive, this study will identify a new potential treatment that is already widely available. The study will also inform on novel mechanistic targets with relevance to existing and future therapeutic strategies.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥40 years old.
  • Ankle-brachial index (ABI) ≤0.90 in at least one leg.
  • Peripheral artery stenosis/occlusion documented by duplex ultrasonography.
  • Stable (i.e. 6-month history) intermittent claudication in at least one PAD-affected leg.
  • Maximum walking time during graded treadmill exercise testing (Gardner-Skinner protocol) ≥1 minute and ≤12 minutes.
  • Pre-diabetes (defined as any of impaired fasting glucose, impaired glucose tolerance, or elevated glycated hemoglobin [HbA1c; that is, in the range 5.7-6.4%]) or non-pharmacologically treated, well-controlled (HbA1c <7.5%) type 2 diabetes.
  • Concurrent medications that may affect primary, secondary or exploratory endpoints have remained stable over the previous 6 months.
  • Have given signed informed consent to participate in the study.

Exclusion Criteria:

  • Identification of any other medical condition requiring immediate therapeutic intervention.
  • Clinically significant abnormal electrocardiogram (ECG), at rest or during exercise.
  • Cardiac disease with symptoms at rest or inducible with exercise.
  • Myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft surgery (CABG), or other major surgery within the previous 6 months.
  • Exercise capacity limited by a factor other than PAD-related intermittent claudication.
  • Any condition that precludes valid completion of a treadmill exercise test.
  • Critical limb ischemia in either leg, defined as PAD-related chronic ischemic rest pain or skin lesions (ulcers, gangrene).
  • Previous peripheral revascularisation or other surgical treatment for PAD in the previous 6 months.
  • Known non-atherosclerotic cause of PAD.
  • History of malignancy within past 5 years (except for non-melanoma skin cancers).
  • Uncontrolled hypertension (resting brachial blood pressure ≥160/100 mmHg).
  • Evidence of pharmacologically-treated or poorly controlled (i.e. HbA1c ≥7.5%) type 2 diabetes or other class of diabetes (e.g. type 1 diabetes).
  • Known intolerance or contraindication(s) to metformin.
  • Contraindication(s) to "Definity" (perflutren lipid microsphere).
  • Participation or intention to participate in a structured and/or supervised physical activity program during the study period.
  • Participation or intention to participate in another clinical research study during the study period.
  • History of non-compliance to medical regimens or unwillingness to comply with the study protocol.
  • Any other condition that in the opinion of the Investigators would confound the evaluation and interpretation of the data.
  • Persons directly involved in the execution of the protocol.
  • Incapable of providing written informed consent due to cognitive, language, or other reasons.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01799057

Contacts
Contact: Julian W Sacre, PhD +61 3 8532 1870 julian.sacre@bakeridi.edu.au
Contact: Bronwyn A Kingwell, PhD +61 3 8532 1518 bronwyn.kingwell@bakeridi.edu.au

Locations
Australia, Victoria
Baker IDI Heart and Diabetes Institute Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Julian W Sacre, PhD    +61 3 8532 1870    julian.sacre@bakeridi.edu.au   
Contact: Bronwyn A Kingwell, PhD    +61 3 8532 1518    bronwyn.kingwell@bakeridi.edu.au   
Principal Investigator: Bronwyn A Kingwell, PhD         
Principal Investigator: Stephen J Duffy, MD, PhD         
Sub-Investigator: Julian W Sacre, PhD         
Sub-Investigator: David A Bertovic, MD         
Sub-Investigator: Mitchell Anderson, MD         
Sub-Investigator: Wayne Childs, MD         
Sub-Investigator: Melissa Formosa, BS         
Sub-Investigator: Jennifer Starr         
Sub-Investigator: Jonathan E Shaw, MD, PhD         
Sub-Investigator: Anna A Ahimastos, PhD         
Sub-Investigator: Adam Lawler         
Sponsors and Collaborators
Baker IDI Heart and Diabetes Institute
Investigators
Principal Investigator: Bronwyn A Kingwell, PhD Baker IDI Heart and Diabetes Institute
Principal Investigator: Stephen J Duffy, MD, PhD Baker IDI Heart and Diabetes Institute
  More Information

No publications provided

Responsible Party: Baker IDI Heart and Diabetes Institute
ClinicalTrials.gov Identifier: NCT01799057     History of Changes
Other Study ID Numbers: 493/12
Study First Received: February 22, 2013
Last Updated: November 3, 2013
Health Authority: Australia: Human Research Ethics Committee
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: National Health and Medical Research Council

Keywords provided by Baker IDI Heart and Diabetes Institute:
Peripheral Arterial Disease
Peripheral Vascular Diseases
Intermittent Claudication
Vascular Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Atherosclerosis
Insulin Resistance
Glucose Metabolism Disorders
Prediabetic State
Diabetes Mellitus, Type 2
Blood Glucose
Metformin
Biguanides
Hypoglycemic Agents
Endothelium, Vascular
Hemorheology
Blood Circulation
Regional Blood Flow
Microcirculation
Exercise
Physical Fitness
Exercise Test
Sedentary Lifestyle
Quality of Life
Plethysmography

Additional relevant MeSH terms:
Peripheral Arterial Disease
Peripheral Vascular Diseases
Intermittent Claudication
Metabolic Diseases
Glucose Metabolism Disorders
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Signs and Symptoms
Atherosclerosis
Hypoglycemic Agents
Metformin
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 20, 2014