The Effects of Metformin on Functional Capacity in Pre-Diabetic Individuals With Peripheral Artery Disease and Intermittent Claudication
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Purpose
The purpose of this study is to determine the effects of metformin on functional capacity (pain-free and maximum walking times) in pre-diabetic individuals with peripheral artery disease (PAD) and intermittent claudication.
| Condition | Intervention | Phase |
|---|---|---|
|
Peripheral Arterial Disease Intermittent Claudication Prediabetic State |
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, Glucose Metabolism, and Hemodynamics in Pre-Diabetic Individuals With Peripheral Artery Disease and Intermittent Claudication |
- 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.
- 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 ]
- 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: | 60 |
| Study Start Date: | February 2013 |
| Estimated Study Completion Date: | January 2016 |
| Estimated Primary Completion Date: | January 2016 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Metformin
Participants randomized to the metformin group will be treated with 500mg metformin (oral capsule) twice per day for 16-18 weeks (up-titrated from 500mg metformin once-daily for the first 1-2 weeks).
|
Drug: Metformin
500mg metformin twice per day for 16-18 weeks (up-titrated from 500mg metformin once-daily for the first 1-2 weeks). Administration will be via oral capsule.
Other Name: Diaformin
|
|
Placebo Comparator: Placebo
Participants randomized to the placebo group will take matching oral capsules with a placebo (lactose powder) twice per day (up-titrated from one capsule per day for the first 1-2 weeks, in accordance with the metformin group).
|
Drug: Placebo
Placebo (lactose power) in matching oral capsule (that is, identical size, shape and color to experimental treatment), taken twice per day (up-titrated from one capsule per day for the first 1-2 weeks).
|
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 typically rely on metformin as part of standard risk factor management (glycemic control), the current study will enrol pre-diabetic individuals with PAD and intermittent claudication. 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 60 pre-diabetic individuals with PAD and intermittent claudication will be randomised (1:1) to either metformin 500mg twice per day (up-titrated from half this dose at 1-2 weeks) or matching placebo for 16-18 weeks (double-blind, parallel group design).
Primary Hypothesis:
Improvement in functional capacity follows metformin therapy in pre-diabetic individuals with PAD and intermittent claudication. 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 |
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%).
- Stable medication regimen 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 (PCTA), coronary artery bypass graft surgery (CABG), or other major surgery within the previous 3 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 limiting leg(s).
- 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 diabetes.
- 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| 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, Victoria | |
| Baker IDI Heart and Diabetes Institute | Not yet 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 | |
| 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: | February 22, 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:
|
Prediabetic State Peripheral Arterial Disease Intermittent Claudication Peripheral Vascular Diseases Vascular Diseases Cardiovascular Diseases Arterial Occlusive Diseases Atherosclerosis Insulin Resistance Glucose Metabolism Disorders 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:
|
Prediabetic State Intermittent Claudication Peripheral Arterial Disease Peripheral Vascular Diseases Arteriosclerosis Arterial Occlusive Diseases Vascular Diseases Cardiovascular Diseases Signs and Symptoms |
Atherosclerosis Diabetes Mellitus Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Hypoglycemic Agents Metformin Physiological Effects of Drugs Pharmacologic Actions |
ClinicalTrials.gov processed this record on May 23, 2013