Peripheral Arterial DiseasePhase 2NCT01401517
Phase IIa: Safety, PK, & Tolerability of Sodium Nitrite in Patients With Peripheral Arterial Disease-SONIC
A Phase 2 study testing sodium nitrite in people with Peripheral Arterial Disease, run by TheraVasc Inc. at 10 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 35 to 85 years
- Conditions the study is for
- Peripheral Arterial Disease
- What is being tested?
- sodium nitrite
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 55 participants
- Where
- 10 sitesUnited States
- Study dates
- Jul 2011to Jan 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 30Show fewer
- 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.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
Emory University
Atlanta, Georgia, 30322
University of Colorado Denver Health Sciences Center
Aurora, Colorado, 80045
University of Cincinnati
Cincinnati, Ohio, 45267
The Cleveland Clinic
Cleveland, Ohio, 44106
University Hospitals
Cleveland, Ohio, 44106
The Ohio State University
Columbus, Ohio, 43210
University of Iowa
Iowa City, Iowa, 52242
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Vanderbilt Heart and Vascular Institute
Nashville, Tennessee, 37232
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
About this study
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.
Read the 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.
- Conditions
- Peripheral Arterial Disease
- Being tested
- sodium nitrite
- Medical subject headings
- Peripheral Arterial Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
sodium nitriteDrug
Also called TV1001
0, 40 or 80 mg twice each day for 10 weeks followed by a 1 week escalation of 2 times the dose.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Microcrystalline cellulose NF at 60 mg/capsule, BID Receives: Drug: sodium nitrite |
| 40 mg Sodium Nitrite | Experimental | 40 mg dose, BID Receives: Drug: sodium nitrite |
| 80 mg Sodium Nitrite | Experimental | 80 mg dose, BID Receives: Drug: sodium nitrite |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reporting of Adverse Events During 11 Week Treatment Period.
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.
Measured: 11 weeks
Secondary outcomes (3)
Assessment of Changes in Brachial Artery Flow-Mediated Dilation (FMD)at 10 Weeks From Baseline
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. FMD was measured at baseline and again after 10 weeks of treatment. The value at ten weeks was subtracted from the baseline value. A negative value represents a worsening of FMD while a positive value represents an improvement in FMD.
Measured: 10 weeks
Assessment of Changes in Walking Distance.
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. Distance walked in 6 minutes was measured at baseline and again after 10 weeks of treatment. The distance walked at ten weeks was subtracted from the baseline distance walked. A negative value represents a worsening of walking distance while a positive value represents an improvement in walking distance.
Measured: 10 weeks
Assessment of Improvement of Quality of Life Using the WIQ (Walking Impairment Questionnaire) and SF-36 Questionnaire.
Demonstrate the pharmacodynamic effect of sodium nitrite on changes in measures of claudication symptoms using Quality of Life questionnaires (WIQ \& RAND SF-36). The WIQ is a disease-specific instrument that measures community-based walking. The questionnaire consists of four subscales (pain severity, distance, speed, and stairs). The SF-36 is a set of 36 questions that the subject provides short answers on concerning general health issues that the subject chooses. Questionnaires were administered at baseline and again after 10 weeks of treatment. Scores from the individual sections were summed and divided by the maximal score for the section to obtain a percent score, ranging from 0 (inability to perform task) to 100 (no difficulty). The scores for each section at ten weeks was subtracted from the baseline scores for each section of the questionnaires. A negative represents declining function, a positive value represents improvement over the study period.
Measured: 10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jul 2011 (estimated)
- Study startJul 2011
- Primary completionJan 2013
- Study completionJan 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Peripheral Arterial DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 55 participants (actual)
Sponsor and investigators
- Lead sponsor
- TheraVasc Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Tony Giordano, Ph.D., Study director, TheraVasc Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01401517
- Sponsor's protocol ID
- TheraVasc-TV1001-002
- Status last verified
- Apr 2020
- First submitted
- 28 Jun 2011
- Last updated
- 21 Apr 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Mohler ER 3rd, Hiatt WR, Gornik HL, Kevil CG, Quyyumi A, Haynes WG, Annex BH. Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: safety, walking distance and endothelial function. Vasc Med. 2014 Feb;19(1):9-17. doi: 10.1177/1358863X13515043. Epub 2013 Dec 20.
PubMed 24363302
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01401517
- Acronym / sponsor ID
- TheraVasc-TV1001-002
- Conditions
- Peripheral Arterial Disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 55 participants (actual)
- Lead sponsor
- TheraVasc Inc.Industry (pharma, biotech, devices)
- Study start
- Jul 2011
- Primary completion
- Jan 2013 (actual)
- Study completion
- Jan 2013 (actual)
- First posted
- 25 Jul 2011 (estimated)
- Results
- Posted 1 Jul 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: sodium nitriteMicrocrystalline cellulose NF at 60 mg/capsule, BID |
| 40 mg Sodium Nitrite | Experimental | Drug: sodium nitrite40 mg dose, BID |
| 80 mg Sodium Nitrite | Experimental | Drug: sodium nitrite80 mg dose, BID |
Who may qualify
- Ages
- 35 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (30 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| sodium nitriteAlso: TV10010, 40 or 80 mg twice each day for 10 weeks followed by a 1 week escalation of 2 times the dose. | Drug | 40 mg Sodium Nitrite, 80 mg Sodium Nitrite, Placebo |
Primary outcome
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.
3 secondary outcomes
Assessment of Changes in Brachial Artery Flow-Mediated Dilation (FMD)at 10 Weeks From Baseline
Time frame: 10 weeks
Assessment of Changes in Walking Distance.
Time frame: 10 weeks
Assessment of Improvement of Quality of Life Using the WIQ (Walking Impairment Questionnaire) and SF-36 Questionnaire.
Time frame: 10 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 24363302Mohler ER 3rd, Hiatt WR, Gornik HL, Kevil CG, Quyyumi A, Haynes WG, Annex BH. Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: safety, walking distance and endothelial function. Vasc Med. 2014 Feb;19(1):9-17. doi: 10.1177/1358863X13515043. Epub 2013 Dec 20.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tony Giordano, Ph.D. study director
TheraVasc Inc.
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing sodium nitrite in people with Peripheral Arterial Disease, run by TheraVasc Inc. at 10 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Jul 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reporting of Adverse Events During 11 Week Treatment Period. (time frame: 11 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01401517, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2020.