Peripheral Arterial DiseasePhase 4NCT01799057
The Effects of Metformin on Functional Capacity in Individuals With Peripheral Artery Disease-Related Intermittent Claudication
A Phase 4 study testing Metformin in people with Peripheral Arterial Disease and Intermittent Claudication, run by Baker Heart and Diabetes Institute at 1 site in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Peripheral Arterial Disease, Intermittent Claudication
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 2 participants
- Where
- 1 siteAustralia
- Study dates
- Jul 2013to Dec 2014
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
Australia1 site
Baker IDI Heart and Diabetes Institute
Melbourne, Victoria, 3004
About this study
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
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.
Read the 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.
- Being tested
- Metformin, Placebo
- 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
- Medical subject headings
- Peripheral Arterial Disease, Intermittent Claudication, Peripheral Vascular Diseases, Vascular Diseases, Cardiovascular Diseases, Arterial Occlusive Diseases, Atherosclerosis, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Diaformin
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.
PlaceboDrug
Participants randomized to placebo will take matching oral capsules according to the same dose schedule specified for the metformin intervention.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Metformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day). Receives: Drug: Metformin |
| Placebo | Placebo comparator | Matching placebo twice daily for 16-18 weeks. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in pain-free walking time
Pain-free walking time (time to onset of claudication) will be measured during a graded treadmill exercise test.
Measured: Measured at baseline and following 16-18 weeks treatment
Change in maximum walking time
Maximum walking time will be measured during a graded treadmill exercise test.
Measured: Measured at baseline and following 16-18 weeks treatment
Secondary outcomes (6)
Change in questionnaire-based markers of quality of life / perceived functional capacity
Measured: Measured at baseline and following 16-18 weeks treatment
Change in endothelial function
Measured: Measured at baseline and following 16-18 weeks treatment
Change in skeletal muscle blood flow response to insulin
Measured: Measured at baseline and following 16-18 weeks treatment
Change in skeletal muscle blood flow response to acute exercise
Measured: Measured at baseline and following 16-18 weeks treatment
Change in insulin sensitivity
Measured: Measured at baseline and following 16-18 weeks treatment
Change in objectively measured physical activity / sedentary behaviour in the daily life setting.
Measured: Measured at baseline and following 16-18 weeks treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2013 (estimated)
- Study startJul 2013
- Primary completionDec 2014
- Study completionDec 2014
Why it stopped: The trial has been terminated due to difficulties with recruitment.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peripheral Arterial DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baker Heart and Diabetes Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Bronwyn A Kingwell, PhD, Principal investigator, Baker Heart and Diabetes InstituteStephen J Duffy, MD, PhD, Principal investigator, Baker Heart and Diabetes Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01799057
- Sponsor's protocol ID
- 493/12
- Status last verified
- Feb 2016
- First submitted
- 22 Feb 2013
- Last updated
- 9 Feb 2016
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01799057
- Acronym / sponsor ID
- 493/12
- Keywords
- Peripheral Arterial Disease, Intermittent Claudication, Peripheral Vascular Diseases, Vascular Diseases, Cardiovascular Diseases, Arterial Occlusive Diseases, Atherosclerosis, Insulin Resistance
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The trial has been terminated due to difficulties with recruitment.
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Baker Heart and Diabetes InstituteUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 26 Feb 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: MetforminMetformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day). |
| Placebo | Placebo comparator | Drug: PlaceboMatching placebo twice daily for 16-18 weeks. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (18 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: DiaforminParticipants 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. | Drug | Metformin |
| PlaceboParticipants randomized to placebo will take matching oral capsules according to the same dose schedule specified for the metformin intervention. | Drug | Placebo |
Primary outcome
Change in pain-free walking time
Time frame: 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
Time frame: Measured at baseline and following 16-18 weeks treatment
Maximum walking time will be measured during a graded treadmill exercise test.
6 secondary outcomes
Change in questionnaire-based markers of quality of life / perceived functional capacity
Time frame: Measured at baseline and following 16-18 weeks treatment
Change in endothelial function
Time frame: Measured at baseline and following 16-18 weeks treatment
Change in skeletal muscle blood flow response to insulin
Time frame: Measured at baseline and following 16-18 weeks treatment
Change in skeletal muscle blood flow response to acute exercise
Time frame: Measured at baseline and following 16-18 weeks treatment
Change in insulin sensitivity
Time frame: Measured at baseline and following 16-18 weeks treatment
Change in objectively measured physical activity / sedentary behaviour in the daily life setting.
Time frame: Measured at baseline and following 16-18 weeks treatment
Results and safety
The study was stopped early (reason given: The trial has been terminated due to difficulties with recruitment.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bronwyn A Kingwell, PhD principal investigator
Baker Heart and Diabetes Institute
Stephen J Duffy, MD, PhD principal investigator
Baker Heart and Diabetes Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Metformin in people with Peripheral Arterial Disease and Intermittent Claudication, run by Baker Heart and Diabetes Institute at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 9 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: The trial has been terminated due to difficulties with recruitment.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in pain-free walking time (time frame: Measured at baseline and following 16-18 weeks treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2016.