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

NCT ID: NCT01799057

Last Updated: 2016-02-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-31
• Study Completion Date: 2014-12-31

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.

Conditions

Peripheral Arterial Disease; Intermittent Claudication

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Metformin

Metformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day).

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

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.

Placebo

Matching placebo twice daily for 16-18 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Participants randomized to placebo will take matching oral capsules according to the same dose schedule specified for the metformin intervention.

Interventions

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.

Intervention Type: DRUG

Placebo

Participants randomized to placebo will take matching oral capsules according to the same dose schedule specified for the metformin intervention.

Intervention Type: DRUG

Other Intervention Names

Diaformin

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.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baker Heart and Diabetes Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bronwyn A Kingwell, PhD

Role: PRINCIPAL_INVESTIGATOR

Baker Heart and Diabetes Institute

Stephen J Duffy, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Baker Heart and Diabetes Institute

Locations

Baker IDI Heart and Diabetes Institute

Melbourne, Victoria, Australia

Countries

Australia

Other Identifiers

493/12

Identifier Type: -

Identifier Source: org_study_id