Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT03493412 |
| Other study ID # |
UNOmaha |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
July 2019 |
| Est. completion date |
October 1, 2019 |
Study information
| Verified date |
August 2023 |
| Source |
University of Nebraska |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
