Peripheral Arterial Disease Clinical Trial
Official title:
A Randomized, Double-blinded, Placebo-controlled, Phase IIa Dose-ranging Study to Assess the Safety, Pharmacokinetics, and Tolerability of Multiple Doses of Sodium Nitrite in Patients With Peripheral Arterial Disease (PAD) - SONIC
Sodium nitrite has been demonstrated to promote new blood vessel growth, speed up wound healing and prevent tissue necrosis in animals. Since patients with PAD experience many of these problems, this study will seek to determine whether this drug, when given orally, could provide the same benefits to patients with PAD.
Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and a strong
predictor of cardiovascular (CV) mortality. The systemic disease of atherosclerosis in these
patients results in arterial stenoses in the arteries supplying the muscles of the lower
extremities. During exercise, the stenoses limit the ability to increase blood flow, which
leads to an oxygen supply/metabolic demand mismatch, a bio-energetic deficit, and subsequent
muscle contractile dysfunction. Thus, the primary pathophysiology of PAD is related to the
limitation in blood flow and abnormal hemodynamics (reduced tissue perfusion pressure and
blood flow) of the lower limbs during exercise. Patients with PAD commonly present with
symptoms of intermittent claudication (IC), often described by patients as a cramping,
aching, or fatigue sensation in the calf muscles of the legs that occurs during physical
activity. Notably, the symptom of claudication pain is due to exercise-induced ischemia in
the muscles of the leg, causing a significant limitation of functional exercise capacity and
adversely affecting quality of life.
Sodium nitrite is being investigated as a potential new therapy for improving function in
patients with PAD. The overall goal of this dose-ranging study is to evaluate the safety,
pharmacokinetics, tolerability, and potential biological activity of multiple doses of oral
sodium nitrite in patients with PAD. As described above, the primary pathophysiology of PAD
is related to the limitation in blood flow of the lower extremities, resulting in limited
exercise tolerance and decreased quality of life. PAD is highly prevalent in patients with
diabetes, leading to poor outcomes and accelerated disease progression compared with
non-diabetic counter-parts. A common feature of both patient groups is endothelial
dysfunction, decreased NO bioavailability, and depletion of NO stores, a finding that may be
compounded when PAD and diabetic conditions coexist. Sodium nitrite is an inorganic salt that
is found and metabolized in vivo. At physiological concentrations, sodium nitrite is known to
cause vasodilation, a feature which is enhanced in hypoxic or ischemic environments. The
nitrite anion acts a NO reservoir and can be readily converted to active NO by a
non-enzymatic reaction with deoxyhemoglobin, making it a unique candidate for potential
therapeutic effect in ischemic tissues. Accordingly, this study is designed to assess the
safety and tolerability of sodium nitrite as well as the pharmacokinetic and pharmacodynamic
relationship of sodium nitrite at two different doses versus placebo. Sodium nitrite's
effects on endothelial function, a marker of NO bioactivity, and measures of functional
walking capacity will also be assessed.
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