Phase IIa: Safety, PK, & Tolerability of Sodium Nitrite in Patients With Peripheral Arterial Disease-SONIC

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01401517
Recruitment Status : Completed
First Posted : July 25, 2011
Results First Posted : July 1, 2014
Last Update Posted : July 1, 2014
Information provided by (Responsible Party):
TheraVasc Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Peripheral Arterial Disease Drug: sodium nitrite Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 55 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Study Start Date : July 2011
Actual Primary Completion Date : January 2013
Actual Study Completion Date : January 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Placebo Comparator: Placebo Drug: sodium nitrite
0, 40 or 80 mg twice each day for 10 weeks followed by a 1 week escalation of 2 times the dose.
Other Name: TV1001

Experimental: 40 mg Sodium Nitrite
40 mg dose, BID
Drug: sodium nitrite
0, 40 or 80 mg twice each day for 10 weeks followed by a 1 week escalation of 2 times the dose.
Other Name: TV1001

Experimental: 80 mg Sodium Nitrite
80 mg dose, BID
Drug: sodium nitrite
0, 40 or 80 mg twice each day for 10 weeks followed by a 1 week escalation of 2 times the dose.
Other Name: TV1001

Primary Outcome Measures :
  1. Reporting of Adverse Events During 11 Week Treatment Period. [ Time Frame: 11 weeks ]
    The primary objective of this clinical study is to evaluate the safety and tolerability of multiple doses of twice daily 40mg and 80mg sodium nitrite compared with placebo over a 10 week treatment period. Subjects will be asked to report any adverse events during the trial period, and blood pressure, methemoglobin levels and other blood chemistries will be assessed during the trial period for changes from baseline.

Secondary Outcome Measures :
  1. Assessment of Changes in Brachial Artery Flow-Mediated Dilation (FMD)at 10 Weeks From Baseline [ Time Frame: 10 weeks ]
    Demonstrate the pharmacodynamic effect of sodium nitrite on changes in FMD by imaging before investigational product administration and 10 weeks after administration of investigational product but before dose escalation.

  2. Assessment of Changes in Walking Distance. [ Time Frame: 10 weeks ]
    Demonstrate the pharmacodynamic effect of sodium nitrite on changes in functional measures of walking distance. The distance a subject can walk in 6 minutes will be measured prior to the first administration of the investigational product and 10 weeks after taking the investigational product but before the dose escalation.

  3. Assessment of Improvement of Quality of Life. [ Time Frame: 10 weeks ]
    Demonstrate the pharmacodynamic effect of sodium nitrite on changes in measures of claudication symptoms at 10 weeks following the first administration of a dose. Quality of Life questionnaires (WIQ & RAND 36)will be completed prior to the first dose of the investigational product and again after 10 weeks of administration but before dose escalation.

Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • The subject is between and including 35 and 85 years of age.
  • Subjects must be either male or females post-menopausal, sterilized or using suitable birth control. Suitable birth control must be total abstinence, male partner sterilization or double barrier method paired with using oral contraception, injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, or intrauterine device (IUD).
  • History of Peripheral Arterial Disease (PAD) confirmed by medical chart or an ankle brachial pressure index at rest ≤0.90.
  • If receiving medical standard treatment for cardiac risk factors, subject must have been on a stable treatment for at least 1 month prior to Screening. Treatments must have not changed significantly in the last month and are not expected to change over the duration of the study.
  • If subjects experience claudication symptoms, subjects must have stable lower extremity symptoms for at least 1 month prior to Screening.
  • Ability to provide written informed consent and willingness as documented by a signed informed consent form.

Exclusion Criteria:

  • Non-atherosclerotic PAD.
  • Lower extremity surgical or percutaneous revascularization, evidence of graft failure or other peripheral vascular surgical procedure within last 6 months prior to Screening.
  • Anticipated lower extremity revascularization within the treatment period.
  • Myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack within 3 months prior to Screening.
  • Poorly controlled diabetes (HgA1c > 10.0).
  • Poorly controlled hypertension (systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg) despite therapy.
  • Systolic blood pressure ≤100 mmHg on current medical regimen.
  • Hypersensitivity to sodium nitrite or related compounds.
  • Renal insufficiency documented as eGFR < 30 mL/minute/1.73 m2.
  • Pregnant or nursing women.
  • Life expectancy < 6 months.
  • A chronic illness that may increase the risks associated with this study in the opinion of the investigator.
  • Active malignancy requiring active anti-neoplastic therapy that will, in the opinion of the investigator, interfere with study treatment or participation.
  • Active infection.
  • NYHA CHF Class III or IV.
  • Recent hospitalization (< 30 days) for acute coronary syndrome, myocardial infarction, congestive heart failure or stroke.
  • Recent (< 30 days) coronary revascularization.
  • Previously treated with angiogenic factors or stem cell therapy within 1 year prior to Screening.
  • Involvement in another PAD clinical trial within past 1 month prior to Screening.
  • Exposed tendon, muscle or bone or a diagnosis of critical leg ischemia.
  • Previous amputation within 3 months prior to Screening or planned amputation that would limit walking (e.g. small toe is allowed).
  • The subject's ability to perform the 6 minute walk test is limited by symptoms other than claudication.
  • Current diagnosis of alcohol or other substance abuse.
  • History of methemoglobinemia, [met-Hb > 15%].
  • Inability to speak English (due to need to administer standardized English-language questionnaire).
  • Evidence of anemia.
  • History of chronic hemolytic condition, including sickle cell disease.
  • Chronic use of anti-migraine medication such as Imitrex or sumatriptan.
  • Have a positive screen for glucose-6-phosphate dehydrogenase deficiency at screening.
  • Subjects who regularly take the following medications: Allopurinol, PDE-5 inhibitors, sedative tricyclic antidepressants, antihistamines, meperidine and related central nervous system depressants, and nitrates.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01401517

United States, Colorado
University of Colorado Denver Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Iowa
University of Iowa
Iowa City,, Iowa, United States, 52242
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45267
The Cleveland Clinic
Cleveland, Ohio, United States, 44106
University Hospitals
Cleveland, Ohio, United States, 44106
The Ohio State University
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Vanderbilt Heart and Vascular Institute
Nashville, Tennessee, United States, 37232
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
TheraVasc Inc.
Study Director: Tony Giordano, Ph.D. TheraVasc Inc.

Responsible Party: TheraVasc Inc. Identifier: NCT01401517     History of Changes
Other Study ID Numbers: TheraVasc-TV1001-002
First Posted: July 25, 2011    Key Record Dates
Results First Posted: July 1, 2014
Last Update Posted: July 1, 2014
Last Verified: May 2014

Additional relevant MeSH terms:
Peripheral Arterial Disease
Peripheral Vascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases