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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Vascular Diseases; Peripheral Artery Disease; Claudication, Intermittent
• Intervention / Treatment: Drug: Tetrahydrobiopterin 10 mg/kg; Drug: L-Ascorbate; Drug: L-Arginine; Drug: Tetrahydrobiopterin 20 mg/kg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Shauneen Valliere, MSN; Phone Number: 508-856-1767; Email: shauneen.valliere@umassmed.edu
• Study Contact Backup: Name: Mollynda McArthur, MS; Phone Number: 508-856-2820; Email: mollynda.mcarthur2@umassmed.edu

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Recruiting
      • UMASS Memorial Healthcare - University Campus
      • Contact: Shauneen Valliere, MSN; Phone Number: 508-856-1767; Email: shauneen.valliere@umassmed.edu
      • Contact: Mollynda McArthur, MS; Phone Number: 508-856-2820; Email: mollynda.mcarthur2@umassmed.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Louis Messina
• Collaborators: BioMarin Pharmaceutical
• Investigators: Principal Investigator: Louis M Messina, MD, UMass Medical School

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2021
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: March 11, 2021
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 16, 2021

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Vascular Diseases; Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Verapamil
• Other Study ID Numbers: H00012734

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes