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

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ClinicalTrials.gov Identifier: NCT03493412
Recruitment Status : Not yet recruiting
First Posted : April 10, 2018
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Song-Young Park, University of Nebraska, Omaha

Tracking Information
First Submitted Date  ICMJE April 3, 2018
First Posted Date  ICMJE April 10, 2018
Last Update Posted Date March 26, 2019
Estimated Study Start Date  ICMJE July 1, 2019
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
Endothelial Function [ Time Frame: 2 days ]
Flow-mediated dilation will be used to measure vasodilation in the brachial artery, and blood flow in the femoral and popliteal arteries
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03493412 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Leg Function [ Time Frame: 2 days ]
    Leg function will be measured with an isokinetic dynamometer
  • Oxidative Stress [ Time Frame: 2 days ]
    Blood draws will be taken to measure oxidative stress markers in the blood
  • Skeletal Muscle Oxygenation [ Time Frame: 2 days ]
    Near-infrared spectroscopy will be used to measure leg muscle oxygenation
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Tetrahydrobiopterin (BH4) on Leg Blood Flow and Exercise Capacity in Patients With Peripheral Artery Disease
Official Title  ICMJE Effects of Tetrahydrobiopterin (BH4) on Leg Blood Flow, Mitochondrial Function and Leg Performance in Patients With Peripheral Artery Disease
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.
Detailed Description According to the National Institute of Health, one in every twenty Americans over the age of 50 years old suffers from peripheral artery disease (PAD). PAD is a manifestation of systemic atherosclerosis and is specifically characterized by atherosclerotic blockages of the arteries in the legs. This results in claudication, a commonly experienced leg pain and immobility due to occlusion of the blood vessels. This pain reduces the amount of physical activity PAD patients can participate in, which can be detrimental to the patient, as it can lead to more systemic issues such as coronary artery disease, heart failure, and metabolic disorders, as well as amputation and death. These periods of occlusion are thought to be caused by endothelial dysfunction in the peripheral arteries leading to the legs, which results in an inability to produce nitric oxide (NO), a potent vasodilator which has been shown to be decreased in patients with PAD. Patients with PAD have also shown higher levels of systemic and skeletal muscle inflammation due to the impaired oxygen transfer capacity of these blood vessels. This inflammation leads to an increase in reactive oxygen species (ROS), which reduce the bioavailability of NO and are closely linked to the vascular dysfunction in PAD. Furthermore, mitochondria, a major cellular component that is responsible for the regulation between levels of production of ROS and antioxidants have shown to be altered in patients with PAD, which may lead to impaired oxygen transfer and utilization capacity, ultimately resulting in claudication, impaired functional capacity and reduced physical activity. 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. Additionally, many cardiovascular diseases have been shown to be highly associated with a reduced bioavailability of NO and a positively associated increase in ROS. These heightened levels of ROS not only reduce the availability of NO, but they may also cause cellular damage within the muscle and cardiovascular system. This combination of a reduced ability of the peripheral blood vessels to dilate due to decreased levels of NO, with a concomitant increased level of inflammation due to higher ROS levels could be extremely detrimental to patients with PAD, as the limited oxygen delivery to skeletal muscles could ultimately result in claudication and reduced physical ability. However, this reduced oxygen delivery and utilization may be able to be improved as previous studies have suggested 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. The findings of this study may help to develop a new clinical therapy for patients with PAD. In this study we will examine endothelial function via flow-mediated dilation, blood flow in the femoral and popliteal arteries with a doppler ultrasound, leg skeletal muscle oxygenation with near-infrared spectroscopy, oxidative stress via blood samples and leg function by conducting a endurance test on an isokinetic dynamometer in 10 class-1 or class-2 PAD patients. We will use 5 mg/kg of BH4 obtained from Biomarin Pharmaceutical Industries in a 1:1 randomized, double-blinded, cross-over design with a 2-week washout period between testing days.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
1:1 Randomized, cross-over, double-blinded design
Masking: Double (Participant, Investigator)
Masking Description:
Double-blinded study
Primary Purpose: Treatment
Condition  ICMJE
  • Peripheral Artery Disease
  • Peripheral Arterial Disease
Intervention  ICMJE
  • Drug: Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin)
    5 mg/kg will be used as the dose of BH4
    Other Name: 6R-BH4
  • Drug: Placebo
    Placebo
    Other Name: Sugar Pill
Study Arms  ICMJE
  • Experimental: BH4-Placebo
    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.
    Interventions:
    • Drug: Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin)
    • Drug: Placebo
  • Experimental: Placebo-BH4
    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.
    Interventions:
    • Drug: Sapropterin Dihydrochloride (BH4, tetrahydrobiopterin)
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2018)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2020
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

Exclusion Criteria:

  1. rest pain or tissue loss due to PAD (Fontaine stage III and IV)
  2. acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma
  3. walking capacity limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03493412
Other Study ID Numbers  ICMJE UNOmaha
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Song-Young Park, University of Nebraska, Omaha
Study Sponsor  ICMJE University of Nebraska, Omaha
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Nebraska, Omaha
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP