The Effects of ATLAS Therapy on Nitric Oxide Bioavailability in Patients With Intermittent Claudication

Study Overview
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Brief Summary
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This study will focus on people with claudication from peripheral arterial disease. The investigators are researching whether a multicomponent therapeutic can increase the production of Nitric Oxide in the blood and whether that leads to an improvement in pain free walking distance and overall physical activity.

Detailed Description
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The primary objective of this study is to show that ATLAS Therapy, (L-Arginine; Tetrahydrobiopterin; L-Ascorbate) is bioavailable in humans and exerts a measurable effect on its in vivo biological signature, Flow Mediated Vasodilation (FMD) in people with intermittent claudication caused by peripheral arterial disease. This will be a Phase I / dose finding study. All subjects will receive 2 different drug doses of the Kuvan the first 45 days they will receive 10 mg/kg/day. The second 45 days they will receive 20/mg/kg/day.

Official Title
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The Effects of ATLAS (Arginine Tetrahydrobiopterin L-Ascorbate) Therapy on Nitric Oxide Bioavailability and Pain-free Walking in Patients With Intermittent Claudication

Conditions
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Claudication, Intermittent, Peripheral Artery Disease, Peripheral Vascular Diseases

Intervention / Treatment
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* Drug: Tetrahydrobiopterin 10 mg/kg
* Drug: Tetrahydrobiopterin 20 mg/kg
* Drug: L-Ascorbate
* Drug: L-Arginine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PAD as demonstrated by an ABI <0 .9 in one leg or TBI less than <0.7 in patients with an ABI >1.3 (non compressible vessels) Rutherford Classification II, III Age >18 years old Willingness to discontinue phosphodiesterase (PDE) 5 inhibitors such as Viagra, Cialis, Levitra, Revatio Willingness to discontinue phosphodiesterase (PDE) 3inhibitors cilostazol, milrinone or Vesnarinone Willing and able to comply with all study procedures Willing and able to provide informed consent Sexually active subjects willing to use an acceptable method of contraception while participating in the study Exclusion Criteria: Hypotension defined as a systolic blood pressure less than 100mmhg systolic at screening or baseline visit Critical Leg Ischemia (Rutherford Classification IV, V, VI) Surgical intervention to alleviate symptoms of claudication in the study leg within the past 6 months or any endovascular interventions within 3 months or who is scheduled to undergo surgical revascularization in the next 6 month Walking limited by reasons other than claudication (e.g. arthritis, lung disease, severe neuropathy, lower extremity amputation except single digits) Serum creatinine >1.5mg/dl or Hepatic enzymes >2X the upper limit of normal Serum potassium greater than 5.0 or use of a potassium sparing diuretic at screening Pregnant, breast feeding or planning to become pregnant (subject or partner) at any time during the study. Myocardial Infarction, Cerebrovascular Accident or deep vein thrombosis within 12 months of screening Known history of nephrolithiasis History of ever having a seizure Concurrent disease or condition that would interfere with study participation or safety such as bleeding disorders, organ transplant, long term immunosuppression (excluding inhaled steroids), current neoplasm or severe gastroesophageal reflux History of vertigo or syncope within the past 10 years Enrollment in another drug or device study within 30 days of screening Required treatment with a drug known to inhibit folate metabolism (e.g. Methotrexate) Taking any of the following medications; PDE3 Inhibitors, PDE5 inhibitors, trental, nitrates, ginkgo biloba, levodopa, warfarin, Axillary lymph node dissection Presence of an amputation except single digits in either leg Preexisting illness that limits ambulation such as severe COPD, class III-IV heart failure, severe arthritis or back pain Glucose-6-dehydrogenase deficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All subjects will receive the same starting dose of the 3 components which will be escalated at day 45.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tetrahydrobiopterin Dose 1 (Day 0 to 44)<br>All subjects will receive 3300mg l-Ascorbate , l-Arginine 3400mg and 10mg/kg of Tetrahydrobiopterin once a day. | Drug: Tetrahydrobiopterin 10 mg/kg<br>* 10mg/kg of Tetrahydrobiopterin daily.<br>* Other names: kuvan;Drug: L-Ascorbate<br>* 3300 mg of l-ascorbate once daily<br>Drug: L-Arginine<br>* 3400mg of l-arginine once daily<br>|
| Experimental: Tetrahydrobiopterin Dose 2 (Day 45 to 90)<br>All subjects will receive 3300mg l-Ascorbate, l-Arginine 3400mg and 20mg/kg of Tetrahydrobiopterin once a day. | Drug: Tetrahydrobiopterin 20 mg/kg<br>* 20mg/kg of Tetrahydrobiopterin daily.<br>* Other names: kuvan;Drug: L-Ascorbate<br>* 3300 mg of l-ascorbate once daily<br>Drug: L-Arginine<br>* 3400mg of l-arginine once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitric Oxide bioavailability | Nitric Oxide bioavailability as measured by flow mediated dilatation (FMD). | 90 days |