What side effects are associated with this type of intervention?

Common treatments for Peripheral Arterial Disease (PAD) include antithrombotic therapy, antiplatelet agents, and therapies aimed at increasing nitric oxide production. Antithrombotic and antiplatelet therapies can lead to bleeding complications, including major or life-threatening bleeding. Specific to nitric oxide production therapies, side effects may include headaches, dizziness, and gastrointestinal issues. Additionally, some patients may experience mild myalgia or transient elevated transaminases. It is important to discuss these potential side effects with a healthcare provider to manage and mitigate risks effectively.

What prior FDA approvals exist?

Several drugs have been approved by the FDA for the treatment of Peripheral Arterial Disease (PAD). Cilostazol, a phosphodiesterase inhibitor, has been approved for improving symptoms of intermittent claudication by increasing blood flow to the limbs. Naftidrofuryl oxalate, another drug used for intermittent claudication, works by improving cellular energy metabolism and blood flow. Statins, such as atorvastatin and simvastatin, are also commonly used in PAD patients to lower cholesterol levels and improve walking distance. While these treatments do not specifically target nitric oxide production, they share the common goal of improving blood flow and reducing symptoms associated with PAD.

What other types of research exist?

Promising novel alternatives for PAD treatment in 2024 include: 1) Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), which have demonstrated cardiovascular benefits in diabetic patients with PAD. 2) PCSK9 inhibitors like evolocumab and alirocumab, which have shown to reduce major adverse limb events and improve cardiovascular outcomes. 3) Supervised exercise therapy, which remains a cornerstone for improving walking distance and overall physical activity in PAD patients. 4) Advanced revascularization techniques, including percutaneous interventions and surgical bypass, tailored to the patient's specific anatomical and clinical needs.

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ATLAS Therapy for Intermittent Claudication (ATLAS Trial)

Q: What is the mechanism of action of this treatment?

Peripheral Arterial Disease (PAD) treatments primarily aim to improve blood flow and alleviate symptoms such as claudication. Common approaches include lifestyle modifications like smoking cessation and exercise, which enhance cardiovascular health, and pharmacotherapies such as statins, ACE inhibitors, and antiplatelet agents that reduce inflammation, lower cholesterol, and prevent clot formation. Revascularization procedures like angioplasty and bypass surgery physically restore blood flow. The focus on increasing nitric oxide (NO) production in treatments is significant because NO dilates blood vessels, improving blood flow and reducing ischemic pain, directly addressing the impaired circulation seen in PAD patients.

Phase 1

Recruiting

Led By Louis M Messina, MD

Research Sponsored by University of Massachusetts, Worcester

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age >18 years old

Willingness to discontinue phosphodiesterase (PDE) 5 inhibitors such as Viagra, Cialis, Levitra, Revatio

Must not have

History of ever having a seizure

Required treatment with a drug known to inhibit folate metabolism (e.g. Methotrexate)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 90 days

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new treatment to help people with pain and difficulty walking due to poor blood flow in their legs. The treatment includes three substances that aim to widen blood vessels and improve circulation. Researchers hope this will reduce pain and allow patients to walk longer distances.

Who is the study for?

Adults over 18 with claudication from peripheral arterial disease (PAD) can join this trial if they have an Ankle-Brachial Index (ABI) <0.9, agree to stop certain medications like Viagra and Cilostazol, and use contraception if sexually active. Excluded are those with severe blood pressure issues, recent heart attacks or strokes, critical leg ischemia, kidney/liver problems, history of seizures or stones in the kidney.

What is being tested?

The study tests whether a combination therapy including Tetrahydrobiopterin at two different doses along with L-Ascorbate and L-Arginine can boost Nitric Oxide production in the blood. This could potentially improve walking distance without pain for those with PAD.

What are the potential side effects?

Potential side effects may include changes in blood pressure or heart rate due to increased Nitric Oxide levels; gastrointestinal discomfort from L-Arginine; risk of kidney stones; and possible interactions leading to altered effectiveness of other medications.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am older than 18 years.

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I am willing to stop taking medications like Viagra or Cialis.

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My leg pain is moderate to severe when walking.

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I have poor blood flow in my legs as shown by specific tests.

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I am willing to stop taking certain heart medications if required.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have had a seizure before.

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I need treatment with a drug that affects vitamin B9 use.

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I have a severe illness like COPD or heart failure that makes it hard for me to walk.

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I have a history of kidney stones.

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I have a G6PD deficiency.

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I haven't had surgery for leg pain while walking in the last 6 months, nor any vessel procedures in the last 3 months, and I'm not scheduled for any.

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I have had vertigo or fainting episodes in the last 10 years.

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I have an amputation in one of my legs, but it's not just a single toe or finger.

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My potassium level is above 5.0 or I am on a medication that saves potassium.

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I have severe leg pain due to poor blood flow.

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I have had surgery to remove lymph nodes under my arm.

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My walking is limited due to conditions other than poor blood flow in my legs.

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I am currently taking medication such as PDE inhibitors, nitrates, or warfarin.

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I haven't had a heart attack, stroke, or deep vein thrombosis in the last year.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 90 days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~90 days

This trial's timeline: 3 weeks for screening, Varies for treatment, and 90 days for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Nitric Oxide bioavailability

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Tetrahydrobiopterin Dose 2 (Day 45 to 90)Experimental Treatment3 Interventions

All subjects will receive 3300mg l-Ascorbate, l-Arginine 3400mg and 20mg/kg of Tetrahydrobiopterin once a day.

Group II: Tetrahydrobiopterin Dose 1 (Day 0 to 44)Experimental Treatment3 Interventions

All subjects will receive 3300mg l-Ascorbate , l-Arginine 3400mg and 10mg/kg of Tetrahydrobiopterin once a day.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Arginine

Not yet FDA approved

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Peripheral Arterial Disease (PAD) treatments primarily aim to improve blood flow and alleviate symptoms such as claudication. Common approaches include lifestyle modifications like smoking cessation and exercise, which enhance cardiovascular health, and pharmacotherapies such as statins, ACE inhibitors, and antiplatelet agents that reduce inflammation, lower cholesterol, and prevent clot formation. Revascularization procedures like angioplasty and bypass surgery physically restore blood flow. The focus on increasing nitric oxide (NO) production in treatments is significant because NO dilates blood vessels, improving blood flow and reducing ischemic pain, directly addressing the impaired circulation seen in PAD patients.

Impaired cross-talk between NO and hyperpolarization in myoendothelial feedback: a novel therapeutic target in early endothelial dysfunction of metabolic disease.Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects.Expression of c-fos, p53 and PCNA in the unstable atherosclerotic carotid plaque.