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

Phase 4

Terminated

• Conditions: Intermittent Claudication; Peripheral Arterial Disease
• Interventions: Drug: Placebo; Drug: Metformin

• Registration Number: NCT01799057
• Lead Sponsor: Baker Heart and Diabetes Institute

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.

Study Timeline

• Study First Submitted: 2013-02-22
• Study First Submitted QC: 2013-02-22
• Study First Posted: 2013-02-26
• Study Start: 2013-07
• Primary Completion: 2014-12
• Study Completion: 2014-12
• Status Verified: 2016-02
• Last Update Submitted: 2016-02-07
• Last Update Posted: 2016-02-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matching placebo twice daily for 16-18 weeks.
Metformin	Metformin	Metformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day).

Primary Outcome Measures

Name	Time	Method
Change in pain-free walking time	Measured at baseline and following 16-18 weeks treatment	Pain-free walking time (time to onset of claudication) will be measured during a graded treadmill exercise test.
Change in maximum walking time	Measured at baseline and following 16-18 weeks treatment	Maximum walking time will be measured during a graded treadmill exercise test.

Secondary Outcome Measures

Name	Time	Method
Change in insulin sensitivity	Measured at baseline and following 16-18 weeks treatment
Change in objectively measured physical activity / sedentary behaviour in the daily life setting.	Measured at baseline and following 16-18 weeks treatment
Change in questionnaire-based markers of quality of life / perceived functional capacity	Measured at baseline and following 16-18 weeks treatment
Change in endothelial function	Measured at baseline and following 16-18 weeks treatment
Change in skeletal muscle blood flow response to insulin	Measured at baseline and following 16-18 weeks treatment
Change in skeletal muscle blood flow response to acute exercise	Measured at baseline and following 16-18 weeks treatment

Trial Locations

Locations (1)

Baker IDI Heart and Diabetes Institute; 🇦🇺 Melbourne, Victoria, Australia