Phase IIa: Safety, PK, & Tolerability of Sodium Nitrite in Patients With Peripheral Arterial Disease-SONIC
Condition: Peripheral Arterial Disease
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): sodium nitrite
Intervention type(s): Drug
Intervention description(s): 0, 40 or 80 mg twice each day for 10 weeks followed by a 1 week escalation of 2 times the dose.
Other intervention name(s): TV1001
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment