Clinical trial NCT01799057: The Effects of Metformin on Functional Capacity in Individuals With Peripheral Artery Disease-Related Intermittent Claudication
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Peripheral Arterial Disease
Intermittent Claudication
Keywords: Peripheral Arterial Disease
Intermittent Claudication
Peripheral Vascular Diseases
Vascular Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Atherosclerosis
Insulin Resistance
Glucose Metabolism
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
Lead sponsor: Baker Heart and Diabetes Institute
Sponsor class: OTHER
First posted: 2013-02-26
Enrollment: 2
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Study Design:

A total of 80 individuals with PAD-related intermittent claudication 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. 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 criteria: Inclusion Criteria:

* Age ≥40 years old.
* Resting ankle-brachial index (ABI) ≤0.90 in the limiting leg(s), or a \>20% reduction in the ABI measured immediately post-exercise where the resting ABI is \>0.90. In cases of incompressible arteries in the limiting leg(s) (i.e. ABI ≥1.40), a toe-brachial index (TBI) of ≤0.70 is required.
* Peripheral artery stenosis/occlusion in the limiting leg(s), documented by duplex ultrasonography or other imaging tests.
* Stable (i.e. 3-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 ≤16 minutes.
* Concurrent medications that may affect primary, secondary or exploratory endpoints have remained stable over the previous 3 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 that represents a contraindication to study procedures or the study drug.
* 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.
* Active cancer.
* 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.
* Known contraindication(s) to "Definity" (perflutren lipid microsphere).
* 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.

Primary outcomes:
measure: Change in pain-free walking time
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in maximum walking time
timeFrame: Measured at baseline and following 16-18 weeks treatment
Secondary outcomes:
measure: Change in questionnaire-based markers of quality of life / perceived functional capacity
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in endothelial function
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in skeletal muscle blood flow response to insulin
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in skeletal muscle blood flow response to acute exercise
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in insulin sensitivity
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in objectively measured physical activity / sedentary behaviour in the daily life setting.
timeFrame: Measured at baseline and following 16-18 weeks treatment
Other outcomes:
measure: Change in glucose uptake and insulin signalling mechanisms in skeletal muscle (exploratory endpoint)
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in skeletal muscle oxidative capacity and substrate utilization (exploratory endpoint)
timeFrame: Measured at baseline and following 16-18 weeks treatment
measure: Change in inflammation, fibrinolysis and coagulation (exploratory endpoint)
timeFrame: Measured at baseline and following 16-18 weeks treatment
Locations:
city: Melbourne
country: Australia
facility: Baker IDI Heart and Diabetes Institute
state: Victoria
Study officials:
affiliation: Baker Heart and Diabetes Institute
name: Bronwyn A Kingwell, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baker Heart and Diabetes Institute
name: Stephen J Duffy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: