Metformin for Intermittent Claudication

(MOBILE IC Trial)

Overseen By Edith I Tzeng, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: VA Office of Research and Development

Must be taking: Statins, Antiplatelets

Must not be taking: Metformin

Disqualifiers: Diabetes, Kidney disease, Pregnancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 18

Duration: 6 months

200 Participants Needed

Trial Summary

What is the purpose of this trial?

Peripheral arterial disease (PAD) affects over 20% of aged adults and is very common among Veterans due significant tobacco use. PAD is due to the progressive blockage of peripheral arteries, predominantly to the legs, and results in intermittent claudication (IC) or recurrent muscle pain with activity secondary to insufficient blood supply. Those with PAD and IC experience a progressive decline in walking and poor quality of life. There is no effective medical treatment for PAD and IC. Metformin is a safe and effective treatment for Type 2 diabetes but it can also reduce inflammation, oxidative stress, and improve energy requirements as well as improve blood flow to the legs. Therefore, the investigators will test the ability of Metformin to improve overall functional status, reduce PAD progression, and reduce systemic inflammation in Veterans suffering from PAD and IC in a randomized, placebo controlled trial: Metformin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC) Trial. The success of this trial may identify a safe and effective treatment for PAD and IC.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that you have been on optimal medical therapy, including statin and anti-platelet therapy, for more than 3 months before joining. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Metformin for treating intermittent claudication?

Metformin, commonly used for Type 2 diabetes, has anti-inflammatory properties that may help improve function and reduce inflammation in patients with intermittent claudication, as suggested by the MOBILE IC trial hypothesis. ^{1 2 3 4 5}

Is metformin generally safe for humans?

Metformin, including its extended-release forms like Glumetza and Glucophage XR, is generally well-tolerated in humans, with studies showing it is safe at doses of 1500 to 2000 mg/day for managing type 2 diabetes. However, it should not be used by people with kidney problems. ^{6 7 8 9 10}

How does the drug Metformin ER differ from other drugs for intermittent claudication?

Metformin ER is unique for intermittent claudication as it is primarily used for managing blood sugar levels in diabetes, unlike other drugs like cilostazol or naftidrofuryl, which are specifically designed to improve walking distance by affecting blood flow. This novel use of Metformin ER could offer a different approach by potentially addressing underlying metabolic issues in patients with both diabetes and intermittent claudication. ^{11 12 13 14 15}

Research Team

Edith I. Tzeng, MD

Principal Investigator

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Eligibility Criteria

This trial is for Veterans over 35 with Peripheral Artery Disease (PAD) and Intermittent Claudication, who have been on optimal medical therapy including lifestyle changes. They must be able to walk a certain distance without severe pain or assistance other than a cane. It's not for those with diabetes, severe kidney disease, recent major surgeries, or conditions limiting walking ability.

Inclusion Criteria

I can walk more than 50 meters but not over 400 meters without severe pain, using only a cane if needed.

I've been on stable heart and blood vessel health treatment for over 3 months, including lifestyle changes.

I am a veteran aged between 35 and 89.

Exclusion Criteria

I have diabetes or my blood sugar levels have been high in the past 6 months.

I cannot swallow pills that are not crushed.

I am scheduled for a major surgery or hospital stay within the next year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Metformin ER 1000mg or placebo daily by mouth for 6 months

6 months

Regular visits and phone calls over 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with main study endpoints assessed at 12 months

12 months

Study visits and phone calls over 12 months

Long-term follow-up

Medical chart review for 5 years to assess long-term outcomes and natural history of IC

5 years

Treatment Details

Interventions

• Metformin ER
• placebo

Trial Overview The MOBILE IC Trial is testing if Metformin ER can improve walking ability and quality of life in PAD patients by reducing inflammation and improving blood flow. Participants will either receive Metformin ER or a placebo in this randomized controlled study.

Participant Groups

Group I: Metformin ER 1000mg Experimental Treatment 1 Intervention

daily by mouth

Group II: Matching placebo Placebo Group 1 Intervention

daily by mouth

Metformin ER is already approved in United States, European Union for the following indications:

Approved in United States as Metformin for:

• Type 2 diabetes mellitus

Approved in European Union as Metformin for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

Northwestern University

Collaborator

Trials

1,674

Recruited

989,000+

San Francisco Veterans Affairs Medical Center

Collaborator

Trials

52

Recruited

211,000+

Findings from Research

The MOBILE IC trial will assess the effects of metformin on 200 non-diabetic veterans with intermittent claudication over 180 days, focusing on improvements in walking distance and overall functional status.

Metformin is hypothesized to reduce systemic inflammation and enhance mitochondrial function, potentially slowing the progression of peripheral artery disease and improving cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol. Reitz, KM., Althouse, AD., Forman, DE., et al.[2023]

Cilostazol was found to be the most effective treatment for increasing both maximum and pain-free walking distances in patients with intermittent claudication, outperforming beraprost and pentoxifylline in a review of 29 randomized controlled trials involving 5352 patients.

While all three treatments (cilostazol, pentoxifylline, and beraprost) were effective, cilostazol and pentoxifylline had a lower incidence of adverse events compared to beraprost, indicating better safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review the efficacy and safety of cilostazol, pentoxifylline, beraprost in the treatment of intermittent claudication: A network meta-analysis. Liang, X., Wang, Y., Zhao, C., et al.[2022]

In a study involving 794 patients with type 2 diabetes and lower extremity arterial disease, adding cilostazol to clopidogrel treatment significantly reduced the risk of ischemic vascular events, such as strokes and heart attacks, compared to clopidogrel alone.

Cilostazol also improved symptoms of intermittent claudication, enhancing walking distance and ankle-brachial index, without increasing the risk of bleeding, making it a safe adjunctive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel-Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events. Kalantzi, K., Tentolouris, N., Melidonis, AJ., et al.[2021]

In a study of 394 patients with intermittent claudication due to peripheral arterial disease, cilostazol 100 mg taken twice daily resulted in a significant 21% improvement in maximal walking distance compared to placebo.

Cilostazol 100 mg also led to a 22% improvement in the distance walked before symptoms appeared, demonstrating its efficacy in alleviating symptoms of intermittent claudication, while the lower dose of 50 mg showed minimal benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Strandness, DE., Dalman, RL., Panian, S., et al.[2018]

Naftidrofuryl oxalate is found to be more effective and less costly than cilostazol and pentoxifylline for treating intermittent claudication due to peripheral arterial disease, with a cost-effectiveness of approximately £6070 per quality-adjusted life year gained.

This analysis challenges previous guidelines that recommended cilostazol, suggesting that naftidrofuryl oxalate is the only vasoactive drug likely to be cost-effective for patients with persistent symptoms despite conventional management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease. Meng, Y., Squires, H., Stevens, JW., et al.[2018]

Metformin extended release (ER) provides effective glycaemic control with once-daily dosing, showing similar effectiveness to twice-daily dosing of immediate-release formulations over a 24-week period in clinical trials.

The metformin ER formulation was well tolerated at doses of 1500 and 2000 mg/day, with no increase in adverse events, indicating its safety for patients managing their blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. Schwartz, SL., Wu, JF., Berner, B.[2019]

Glumetz (M-ER) is a newly approved extended-release formulation of metformin that provides effective and sustained glycemic control with once-daily dosing, showing similar bioavailability to immediate-release metformin taken twice daily.

In clinical trials lasting 24 weeks, M-ER demonstrated good efficacy and was well tolerated, with continued glycemic control maintained in an additional 24-week open-label extension study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. Schwartz, SL., Gordi, T., Hou, E., et al.[2013]

A comprehensive analysis of 15 clinical studies involving 6638 patients showed that liraglutide, a GLP-1 receptor agonist, had a lower incidence of major adverse cardiovascular events (MACE) compared to other diabetes treatments, with an incidence ratio of 0.73.

The study confirmed that liraglutide's cardiovascular safety profile is within the limits set by the FDA for diabetes therapies, indicating it is a safe option for patients at risk of cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Marso, SP., Lindsey, JB., Stolker, JM., et al.[2022]

The new extended-release formulation of metformin (Glucophage XR) allows for once-daily dosing, which is more convenient compared to the conventional immediate-release version that requires two to three doses per day.

In a study with 16 healthy volunteers, metformin XR was found to be well tolerated at doses up to 2000 mg once daily, with pharmacokinetic properties similar to those of the immediate-release formulation, indicating it can effectively manage blood sugar levels without significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steady-state pharmacokinetics of a novel extended-release metformin formulation. Timmins, P., Donahue, S., Meeker, J., et al.[2022]

In a post hoc analysis of the REWIND trial involving 824 participants with major adverse cardiovascular events (MACE), dulaglutide treatment was linked to a significant reduction in biomarkers associated with heart stress (NT-proBNP) and inflammation (GDF-15), suggesting its potential cardiovascular protective effects.

Higher levels of NT-proBNP and GDF-15 were found to be associated with an increased risk of MACE, indicating that monitoring these biomarkers could help assess cardiovascular risk in patients treated with dulaglutide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis. Gerstein, HC., Lee, SF., Paré, G., et al.[2023]

Patients with intermittent claudication treated with PGE1 alpha-ciclodestrina showed significant improvements in walking distance, including those with diabetes, indicating its efficacy in enhancing mobility.

In patients with critical ischemia, treatment with PGE1 alpha-ciclodestrina resulted in no major amputations and only 2 minor amputations, compared to 10.6% major amputations in the control group, highlighting its potential to preserve limbs and improve quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of costs and results of prostaglandin (PGE1 alpha-cyclodestrin) therapy of peripheral arterial diseases]. Bucci, M., Iacobitti, P., Laurora, G., et al.[2013]

A multicenter trial in Argentina involving 615 patients with intermittent claudication aimed to confirm the efficacy of ticlopidine, a platelet aggregation inhibitor, in reducing thrombotic events in patients with atherosclerotic disease of the lower limbs.

Patients were treated with either ticlopidine (500 mg/day) or a placebo for 24 weeks, with the study designed to include both diabetic and non-diabetic participants, highlighting its potential applicability across different patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease in Argentina. Design, organization and general characteristics of patients at entry. The EMATAP Group. Blanchard, JF., Carreras, LO.[2013]

Oral vasoactive drugs like naftidrofuryl and cilostazol have been shown to safely increase walking capacity in patients with intermittent claudication, supported by systematic reviews and meta-analyses, leading to their inclusion in treatment recommendations for peripheral arterial disease.

In contrast, buflomedil and pentoxifylline have limited evidence for effectiveness and safety concerns, indicating that vasoactive drugs should not replace lifestyle changes or exercise therapy but can serve as adjunct treatments when other options are not viable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Silence of the limbs pharmacological symptomatic treatment of intermittent claudication. De Backer, T., Vander Stichele, R., De Buyzere, M., et al.[2019]

For patients with intermittent claudication, non-interventional therapies are preferred over immediate surgical options, as they are at a lower risk for limb loss compared to those with chronic critical limb ischemia.

Cilostazol, a medication that inhibits phosphodiesterase III, has been shown to significantly improve walking distance and quality of life for claudicants, making it the most effective pharmacotherapy currently available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic treatment for intermittent claudication. Dean, SM.[2017]

In a study involving 21 patients with stable intermittent claudication, ketanserin treatment for three months did not lead to significant improvements in claudication time or total walking time, indicating limited efficacy.

The results suggest that ketanserin is unlikely to provide clinically meaningful benefits for patients suffering from intermittent claudication, as the changes observed were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of ketanserin in the treatment of intermittent claudication. Cameron, HA., Waller, PC., Ramsay, LE.[2017]

References

1. England pubmed.ncbi.nlm.nih.gov

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Systematic review the efficacy and safety of cilostazol, pentoxifylline, beraprost in the treatment of intermittent claudication: A network meta-analysis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel-Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Steady-state pharmacokinetics of a novel extended-release metformin formulation. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis. [2023]

11. Italy pubmed.ncbi.nlm.nih.gov

[Analysis of costs and results of prostaglandin (PGE1 alpha-cyclodestrin) therapy of peripheral arterial diseases]. [2013]

12. Germany pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease in Argentina. Design, organization and general characteristics of patients at entry. The EMATAP Group. [2013]

13. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Silence of the limbs pharmacological symptomatic treatment of intermittent claudication. [2019]

14. England pubmed.ncbi.nlm.nih.gov

Pharmacologic treatment for intermittent claudication. [2017]

15. United States pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of ketanserin in the treatment of intermittent claudication. [2017]