Effects of Tetrahydrobiopterin (BH4) on Leg Blood Flow and Exercise Capacity in Patients With Peripheral Artery Disease

NCT03493412 | Withdrawn Phase 4 FDA Drug

• 1 other identifier: UNOmaha
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Nitric oxide has been shown to be an important regulator within the cardiovascular system, responsible for regulation of blood flow, blood pressure and vascular growth. Cardiovascular diseases show a reduced ability of the peripheral blood vessels to dilate due to decreased levels of NO with concomitant increased levels of oxidative stress, which is extremely detrimental to patients with PAD, as the limited oxygen delivery to skeletal muscles ultimately results in claudication and reduced physical ability. However, this reduced oxygen delivery and utilization may be able to be improved as previous studies have revealed that tetrahydrobiopterin (BH4), is an important cofactor responsible for NO production. Furthermore, recent studies have shown that endothelial BH4 levels are associated with the vascular pathophysiological response to hypoxia, as it directly mediates endothelial nitric oxide synthase regulation and reduces superoxide production. Additionally, acute administration of BH4 was shown to improve vascular function, specifically, endothelial mediated vasodilatory function, in patients with systemic vascular and coronary disease, as well as six minute walking distances in patients with hypertension. Therefore, the purpose of this proposed study will be to examine the effects of BH4 on vascular function, oxidative stress and leg performance in patients with PAD. This study will examine patients with a classification of stage 1 or stage 2 peripheral artery disease who demonstrate a history of exercise-limiting claudication. Blood vessel oxygen transfer capacity in the leg will be assessed in the femoral and popliteal arteries with ultrasound, and blood vessel dilatory ability will be assessed in the brachial artery with flow-mediated dilation. Skeletal muscle mitochondrial function will be measured with near infrared spectroscopy, and ROS levels will be analyzed through blood samples. Leg function will be measured with an isokinetic dynamometer.

Conditions

Peripheral Artery Disease; Peripheral Arterial Disease

Outcome Measures

Primary Outcomes (1)

• Endothelial Function

  Flow-mediated dilation will be used to measure vasodilation in the brachial artery, and blood flow in the femoral and popliteal arteries

  2 days

Secondary Outcomes (3)

• Leg Function

  2 days

• Oxidative Stress

  2 days

• Skeletal Muscle Oxygenation

  2 days

Study Arms (2)

BH4-Placebo

EXPERIMENTAL

Subjects will be tested on two different days, first day will be baseline and Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin) and second day will be Placebo. Testing will take place one-hour after BH4/placebo intake. There will be a 2-week washout between testing days.

Drug: Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin); Drug: Placebo

Placebo-BH4

EXPERIMENTAL

Subjects will be tested on two different days, first day will be baseline and placebo and second day will be Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin). Testing will take place one-hour after BH4/placebo intake. There will be a 2-week washout between testing days.

Drug: Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin); Drug: Placebo

Interventions

Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin) DRUG

5 mg/kg will be used as the dose of BH4

Also known as: 6R-BH4

BH4-Placebo; Placebo-BH4

Placebo DRUG

Placebo

Also known as: Sugar Pill

BH4-Placebo; Placebo-BH4

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• be able to give written, informed consent
• demonstrate positive history of chronic claudication
• have a history of exercise limiting claudication
• have an ankle/brachial index \< 0.90 at rest
• have a stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks.
• be between 50-85 years old

You may not qualify if:

• rest pain or tissue loss due to PAD (Fontaine stage III and IV)
• acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma
• walking capacity limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology

Sponsors & Collaborators

• University of Nebraska: lead

MeSH Terms

Conditions

Peripheral Arterial Disease

Interventions

sapropterin; Sugars

Condition Hierarchy (Ancestors)

Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases

Intervention Hierarchy (Ancestors)

Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blinded study
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 1:1 Randomized, cross-over, double-blinded design

Study Record Dates

• First Submitted: April 3, 2018
• First Posted: April 10, 2018
• Study Start: July 1, 2019
• Primary Completion: July 1, 2019
• Study Completion: October 1, 2019
• Last Updated: September 3, 2024

Record last verified: 2024-08