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

February 22, 2013
November 3, 2013
July 2013
June 2016   (final data collection date for primary outcome measure)
  • 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.
Same as current
Complete list of historical versions of study NCT01799057 on ClinicalTrials.gov Archive Site
  • 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 ]
Same as current
  • 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 ]
Same as current
 
The Effects of Metformin on Functional Capacity in Individuals With Peripheral Artery Disease-Related Intermittent Claudication and Abnormal Glucose Metabolism
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

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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Peripheral Arterial Disease
  • Intermittent Claudication
  • Glucose Metabolism Disorders
  • 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
  • Drug: Placebo
    Participants randomized to placebo will take matching oral capsules according to the same dose schedule specified for the metformin intervention.
  • Experimental: Metformin
    Metformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day).
    Intervention: Drug: Metformin
  • Placebo Comparator: Placebo
    Matching placebo twice daily for 16-18 weeks.
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
80
June 2016
June 2016   (final data collection date for primary outcome measure)

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.
Both
40 Years and older
No
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
Australia
 
NCT01799057
493/12
No
Baker IDI Heart and Diabetes Institute
Baker IDI Heart and Diabetes Institute
Not Provided
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
Baker IDI Heart and Diabetes Institute
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP