Peripheral Artery DiseasePhase 4NCT01901224
Metformin, Muscle Energetics, and Vascular Function in Older Adults With Peripheral Artery Disease
A Phase 4 study testing Metformin 1000 mg in people with Peripheral Artery Disease, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
The investigators are doing this research study to find out if taking Metformin improves walking ability in patients with peripheral arterial disease (PAD). In PAD the arteries (blood vessels) in the legs are narrowed because of the build up of plaque. Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Peripheral Artery Disease
- What is being tested?
- Metformin 1000 mg
- 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 siteUnited States
- Study dates
- Jul 2013to Jun 2015
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 or greater
- Intermittent claudication for 6 months or greater
- Maximal walk time between 1-20 minutes on all ETTs
- Resting ABI ≤ 0.9 in index leg at baseline
- ABI falls ≥ 20% in index leg 1 minute post baseline ETT
- MWT variability < 20%
Who cannot join
- Type 1 or Type 2 Diabetes
- Limb-threatening ischemia (rest pain, ulceration, gangrene)
- Peripheral vascular surgery or PCI within 6 months
- MI or CABG within 6 months
- Carotid endarterectomy (CEA) within 6 months
- Cerebrovascular accident or TIA within 6 months
Show all 13Show fewer
- Uncontrolled hypertension (SBP > 140 mmHg, DBP >90 mmHg)
- Pentoxifylline/Cilostazol added/changed within 3 months
- HMG-CoA reductase inhibitor added/changed within 3 months
- Exercise limitations other than claudication (heart failure, angina, COPD, arthritis, neuropathy, etc.)
- Serum creatinine ≥ 1.5 mg/dL
- Pregnant or plans to become pregnant
- 2 hour Oral Glucose Tolerance Test (OGTT) > 200 mg/dL
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02115
About this study
The investigators are doing this research study to find out if taking Metformin improves walking ability in patients with peripheral arterial disease (PAD). In PAD the arteries (blood vessels) in the legs are narrowed because of the build up of plaque. The leg muscle can hurt in patients with PAD and this is usually described as a cramp or tiredness. This pain is called intermittent claudication. Metformin is an FDA approved medication for the treatment of diabetes. The investigators believe that Metformin may help your leg muscles work better.
The investigators will enroll up to 100 subjects in order to find 60 subjects with PAD at Brigham and Women's Hospital (BWH).
Read the detailed description
Peripheral artery disease (PAD) is a manifestation of atherosclerosis that affects more than 7 million adults in the US. The prevalence of PAD increases with age and is estimated to be 15 20% among individuals 65 years of age and older. Patients with PAD have limited functional capacity; they walk more slowly and have less walking endurance than persons who do not have PAD, irrespective of whether they have classic symptoms of intermittent claudication or critical limb ischemia. This functional impairment adversely affects quality of life. Although flow limitation due to atherosclerotic stenosis is necessary for the development of symptoms in PAD, the lack of correlation between walking capacity and the degree of hemodynamic compromise raises the possibility that alternative mechanisms contribute to functional limitations in these patients. Putative mechanisms include inadequate skeletal muscle glucose uptake, altered skeletal muscle energetics, and impaired vasomotor tone and nutrient delivery mediated by endothelial dysfunction. Metformin, via AMPactivated protein kinase (AMPK)-dependent and independent mechanisms, can favorably affect skeletal muscle metabolic functions including glucose uptake, fatty acid oxidation, mitochondrial function, and consequently cellular energetics, and it also may have a direct salutary effect on vascular function via regulation of nitric oxide synthase. It is intriguing, therefore, to consider the possibility that metformin would improve skeletal muscle metabolic and vascular function in older patients with PAD and translate into functional benefits. Accordingly, the investigators seek to elucidate molecular mechanisms through which metformin affects skeletal muscle energetics and hypothesize that metformin will lead to advantageous metabolic, vascular, and physical functional changes in older patients with PAD.
- Conditions
- Peripheral Artery Disease
- Being tested
- Metformin 1000 mg, Placebo
- Medical subject headings
- Peripheral Arterial Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin 1000 mgDrug
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Metformin 1000 mg | Experimental | metformin 1000 mg twice daily: In order to avoid gastrointestinal side effects, the starting dose of metformin will be 500 mg twice daily. After one week, the dose will be increased to 1000 mg twice daily (as two 500 mg tablets twice daily). Subjects will be instructed to take medications with breakfast and with dinner. Receives: Drug: Metformin 1000 mg |
| Control | Placebo comparator | placebo twice daily: In order to maintain blinding during the titration period, individuals randomized to placebo will receive one placebo tablet twice daily for one week, followed by an increase to 2 placebo tablets twice daily. Subjects will be instructed to take medications with breakfast and with dinner. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in PCr Recovery Time
PCr recovery time, measured in seconds, is a measure of skeletal muscle metabolic function. PCr is a transport molecule and reservoir of high-energy phosphate bonds, which is important for cellular energetics. Phosphocreatine regeneration depends upon the skeletal muscle mitochondrial cells capacity for oxidative phosphorylation. We will measure PCr recovery time at baseline and after 12 weeks of treatment with metformin or placebo as an in vivo measure of mitochondrial function. Higher Pcr relative to P(i) during recovery is better and shorter recovery times are better.
Measured: baseline, 12 weeks
Secondary outcomes (1)
Change in Flow-mediated Dilation (FMD)
Flow mediated vasodilation of the brachial artery is a measure of endothelium-dependent vasodilation. Higher flow-mediated dilation (FMD), measured as the diameter of the brachial artery in millimeters, and reported as percent change after a flow stimulus compered to basal measurement, is better, indicative of better endothelial function.
Measured: baseline, 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jul 2013 (estimated)
- Study startJul 2013
- Primary completionJun 2015
- Study completionJun 2015
Why it stopped: study was not funded
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Peripheral Artery DiseaseStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
- 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
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mark Alan Creager, MD, Brigham and Women's Hospital
- Investigators
- Mark A Creager, MD, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01901224
- Sponsor's protocol ID
- 2013P001042
- Status last verified
- Sep 2018
- First submitted
- 12 Jul 2013
- Last updated
- 24 Sep 2018
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metformin, Muscle Energetics, and Vascular Function in Older Adults With Peripheral Artery Disease
- ClinicalTrials.gov ID
- NCT01901224
- Acronym / sponsor ID
- 2013P001042
- Conditions
- Peripheral Artery Disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: study was not funded
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 17 Jul 2013 (estimated)
- Results
- Posted 24 Sep 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators are doing this research study to find out if taking Metformin improves walking ability in patients with peripheral arterial disease (PAD). In PAD the arteries (blood vessels) in the legs are narrowed because of the build up of plaque. The leg muscle can hurt in patients with PAD and this is usually described as a cramp or tiredness. This pain is called intermittent claudication. Metformin is an FDA approved medication for the treatment of diabetes. The investigators believe that Metformin may help your leg muscles work better.
The investigators will enroll up to 100 subjects in order to find 60 subjects with PAD at Brigham and Women's Hospital (BWH).
Detailed description
Peripheral artery disease (PAD) is a manifestation of atherosclerosis that affects more than 7 million adults in the US. The prevalence of PAD increases with age and is estimated to be 15 20% among individuals 65 years of age and older. Patients with PAD have limited functional capacity; they walk more slowly and have less walking endurance than persons who do not have PAD, irrespective of whether they have classic symptoms of intermittent claudication or critical limb ischemia. This functional impairment adversely affects quality of life. Although flow limitation due to atherosclerotic stenosis is necessary for the development of symptoms in PAD, the lack of correlation between walking capacity and the degree of hemodynamic compromise raises the possibility that alternative mechanisms contribute to functional limitations in these patients. Putative mechanisms include inadequate skeletal muscle glucose uptake, altered skeletal muscle energetics, and impaired vasomotor tone and nutrient delivery mediated by endothelial dysfunction. Metformin, via AMPactivated protein kinase (AMPK)-dependent and independent mechanisms, can favorably affect skeletal muscle metabolic functions including glucose uptake, fatty acid oxidation, mitochondrial function, and consequently cellular energetics, and it also may have a direct salutary effect on vascular function via regulation of nitric oxide synthase. It is intriguing, therefore, to consider the possibility that metformin would improve skeletal muscle metabolic and vascular function in older patients with PAD and translate into functional benefits. Accordingly, the investigators seek to elucidate molecular mechanisms through which metformin affects skeletal muscle energetics and hypothesize that metformin will lead to advantageous metabolic, vascular, and physical functional changes in older patients with PAD.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin 1000 mg | Experimental | Drug: Metformin 1000 mgmetformin 1000 mg twice daily: In order to avoid gastrointestinal side effects, the starting dose of metformin will be 500 mg twice daily. After one week, the dose will be increased to 1000 mg twice daily (as two 500 mg tablets twice daily). Subjects will be instructed to take medications with breakfast and with dinner. |
| Control | Placebo comparator | Drug: Placeboplacebo twice daily: In order to maintain blinding during the titration period, individuals randomized to placebo will receive one placebo tablet twice daily for one week, followed by an increase to 2 placebo tablets twice daily. Subjects will be instructed to take medications with breakfast and with dinner. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Age 40 years or greater
- Intermittent claudication for 6 months or greater
- Maximal walk time between 1-20 minutes on all ETTs
- Resting ABI ≤ 0.9 in index leg at baseline
- ABI falls ≥ 20% in index leg 1 minute post baseline ETT
Key exclusion criteria (13 listed)
- Type 1 or Type 2 Diabetes
- Limb-threatening ischemia (rest pain, ulceration, gangrene)
- Peripheral vascular surgery or PCI within 6 months
- MI or CABG within 6 months
- Carotid endarterectomy (CEA) within 6 months
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 |
|---|---|---|
| Metformin 1000 mg | Drug | Metformin 1000 mg |
| Placebo | Drug | Control |
Primary outcome
Change in PCr Recovery Time
Time frame: baseline, 12 weeks
PCr recovery time, measured in seconds, is a measure of skeletal muscle metabolic function. PCr is a transport molecule and reservoir of high-energy phosphate bonds, which is important for cellular energetics. Phosphocreatine regeneration depends upon the skeletal muscle mitochondrial cells capacity for oxidative phosphorylation. We will measure PCr recovery time at baseline and after 12 weeks of treatment with metformin or placebo as an in vivo measure of mitochondrial function. Higher Pcr relative to P(i) during recovery is better and shorter recovery times are better.
1 secondary outcome
Change in Flow-mediated Dilation (FMD)
Time frame: baseline, 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Mark A Creager, MD principal investigator
Brigham and Women's Hospital
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 1000 mg in people with Peripheral Artery Disease, run by Brigham and Women's Hospital at 1 site in United States.
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 6 inclusion and 13 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 24 Sep 2018. 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 United States. 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?
Yes. Results are posted in the registry (first posted 24 Sep 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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 PCr Recovery Time (time frame: baseline, 12 weeks). 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 24 Sep 2018.