HealthyPhase 1NCT00103025
Nitrite Infusion in Healthy Volunteers
A Phase 1 study testing Sodium Nitrite and Sodium Nitrite Injection in people with Healthy, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial summary
This study will determine the dose of sodium nitrite that can safely be used to prevent constriction, or tightening, of the arteries. Narrowed arteries in the brain can cause stroke. Read more about this study
- Who is it for?
- Ages 21 to 60 years
- Conditions the study is for
- Healthy
- What is being tested?
- Sodium Nitrite and Sodium Nitrite Injection
- Type of treatment
- Injection or infusion
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 4 Feb 2005to 10 May 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 21 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Subjects must be 21-60 years of age.
- Subjects must be in good health.
- Subjects must provide informed, written consent for participation in this study.
- Female subjects of childbearing age must have a negative pregnancy test and agree to participate in assessment of menstrual cycle duration before, during, and after infusion.
- Subjects must be willing to temporarily stop any medications (except oral contraception), vitamin supplements, herbal medicines.
- Subjects will have hemoglobin levels above 11.1 g/dL.
Who cannot join
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 130 mg/dL), or diabetes mellitus (fasting blood glucose greater than 126 mg/dL).
- Subjects who have a history of smoking within two years.
- Subjects who have a history of cardiovascular disease, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- Subjects with red blood cell G6PD deficiency (levels below the lower limits of normal).
- Subjects with a history of reaction to a medication or other substance characterized by dyspnea and cyanosis.
- Subjects with a baseline methemoglobin level greater than 1%.
Show all 10Show fewer
- Pregnant women, since nitrite may cross the placenta; nitrite effect on fetus is unknown and mother's methemoglobinemia may be dangerous to the fetus.
- Breast-feeding females, since nitrite crosses into breast milk and could cause methemoglobinemia in the infant.
- Subjects with a blood pressure of less than 100/70 mmHg on the study day.
- Subjects treated with nitrates (e.g. nitroglycerin).
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Long-Term Intravenous Nitrite Infusion in Healthy Volunteers
This study will determine the dose of sodium nitrite that can safely be used to prevent constriction, or tightening, of the arteries. Narrowed arteries in the brain can cause stroke. Animal studies show that nitrite injections improve blood flow and that injections over long periods of time prevent damage to the arteries in the brain; however, there is no information on the effects of prolonged nitrite infusion in humans. This study will establish the safe dose and side effects of nitrite infusion in humans.
Healthy normal volunteers between 21 and 60 years of age may be eligible for this study. Candidates are screened for high or low blood pressure, aspirin use, pregnancy, and blood levels of nitrite and methemoglobin (a substance that temporarily and slightly lowers the oxygen carried in the red blood cells). Pregnant women are excluded from the study.
Read more
Participants are admitted to the Clinical Center for 16 1/4 days, the first 2 days in the hospital's intensive care unit (ICU). Upon admission they provide a medical history, have physical and cardiovascular examinations, and blood tests. For the infusion procedure, a catheter (thin plastic tube) is inserted into an artery in the wrist or the crease of the elbow to measure blood pressure, and catheters are placed in a vein in each arm for administering the nitrite and withdrawing blood samples.
In the morning of day 1, after initial blood pressure and heart rate measurements are taken and a blood sample is drawn, a saline (salt water) infusion is started. Blood pressure and heart rate are monitored every 30 minutes for 6 hours, then every hour for 6 hours, then every 2 hours for 12 hours. Blood samples are collected every 4 hours for 24 hours. On day 2, the sodium nitrite infusion begins. Blood pressure and methemoglobin are monitored every 10 minutes for the first 2 hours. If blood pressure remains stable, the frequency of measurements is decreased to every 30 minutes for 4 hours, then every 1 hour for the next 6 hours, and then every 4 hours for 12 hours. If the pressure continues to remain stable, monitoring continues every 8 hours for the rest of the study. Blood is drawn periodically from the catheter to determine the amount of nitrite and methemoglobin in the body, with decreasing frequency from several times during the first hour of the infusion to every 24 hours. After the first 24 to 48 hours of the nitrite infusion, participants are transferred from the ICU to a general nursing unit fo...
Read the detailed description
Nitric oxide (NO) is beneficial in treatment of many animal models of diseases like heart and brain ischemia, reperfusion injury, and delayed cerebral vasospasm after subarachnoid hemorrhage. It also has been shown to open blood-brain barrier facilitating transfer of chemotherapeutic agents, dilate constricted pulmonary arteries, and inhibit apoptosis, as well as modulate angiogenesis. Until recently, all these biological effects were attributed to the regional synthesis of nitric oxide by the endothelium and its local influence of vascular tone. However, "NO bioactivity" may be transported in blood and have biological effects at a distance from the site of entry into the circulation. These effects of NO are mediated by intravascular NO-stores. Candidates are protein and heme-bound NO species (RXNO) in plasma or erythrocytes and the oxidative NO-metabolite nitrite. Cumulating evidence suggests that nitrite may serve as a major intravascular storage pool for NO. Recent studies have shown that (1) regional, intra-arterial infusion of nitrite elicits a downstream vasodilator response in humans and (2) intravenous long-lasting administration prevents development of delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). These studies suggest a potential new therapeutic approach to many diseases. Despite extensive data documenting the pharmacokinetics and safety of the bolus and short intravascular infusions of nitrite, there are no human data evaluating safety and toxicity of prolonged delivery of nitrite, which would be required for treatment of vascular diseases.
OBJECTIVES
This study has the following objectives: (1) to determine the safety and (2) toxicity of a 48-hour and 14-day intravenous infusion of nitrite. The study should also help to elucidate the mechanism(s) through which nitrite ions contribute to vasodilation.
STUDY POPULATION
The study population will include sixteen 48-hour infusion healthy volunteers (out of 40 screened volunteers) of both genders, age 21-60, who will have a continuous intravenous infusion of sodium nitrite (the source of the drug will be determined by a CRADA).
DESIGN
This is a Phase I toxicity study of intermediate (48-hour) intravenous infusion of sodium nitrite in healthy volunteers.
OUTCOME MEASURES
Sixteen healthy volunteers of both genders, age 21-60, will have a 48-hour continuous intravenous infusion of sodium nitrite during which the subjects' clinical condition, blood levels of nitrite/methemoglobin, hematology, blood chemistry, and pressure will be meticulously monitored.
The first subject will receive the sodium nitrite infusion at 12 mg/48 hours. This dose, according to our knowledge from the former studies and detailed analysis of pharmacokinetics of sodium nitrite, will result in blood levels of sodium nitrite below 80 nmol/L, levels that are significantly below levels reported as normal (0.5 micromol/L to 1 micromol/L). Thus, we will use the modified accelerated titration design for Phase I Clinical studies. In the accelerated design the initial patient will start with the dose 1 nmol/min/kg/48hr, i.e. 12 mg total over 48 hours for a person weighting 60 kg. Cohorts of one new subject per dose level and double dose steps will be used during the initial accelerated stage. When the first instance of dose-limiting toxicity (DLT) is observed at any dose level, the next lower dose level cohort will be expanded to three patients and revert to the use of conventional modified Fibonacci escalation/de-escalation. If no DLT is observed at level 10, the cohort will be expanded to a total of three and de-escalated as appropriate. If no more than one subject among three patients experience DLT at this dose, level 10 will be considered to be the maximum tolerated dose (MTD).
The results of this 48-hour infusion phase 1 trial will be submitted to FDA before initiation of a 14-day clinical study.
- Conditions
- Healthy
- Being tested
- Sodium Nitrite, Sodium Nitrite Injection
- Keywords
- Vasodilation, Hypotension, Hypertension, EDRF, Methemoglobinemia, Healthy Volunteer, HV
- Medical subject headings
- Aneurysm, Hypotension, Hypertension, Methemoglobinemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium NitriteDrug
Sodium Nitrite InjectionDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Feb 2005 (estimated)
- Study start4 Feb 2005
- Primary completion10 May 2011
- Study completion10 May 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies 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 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00103025
- Sponsor's protocol ID
- 050075
- Other IDs
- 05-N-0075
- Status last verified
- 10 May 2011
- First submitted
- 5 Feb 2005
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Afshar JK, Pluta RM, Boock RJ, Thompson BG, Oldfield EH. Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg. 1995 Jul;83(1):118-22. doi: 10.3171/jns.1995.83.1.0118.
PubMed 7782826Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003 Dec;9(12):1498-505. doi: 10.1038/nm954. Epub 2003 Nov 2.
PubMed 14595407Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
PubMed 6253831Pluta RM, Oldfield EH, Bakhtian KD, Fathi AR, Smith RK, Devroom HL, Nahavandi M, Woo S, Figg WD, Lonser RR. Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers. PLoS One. 2011 Jan 10;6(1):e14504. doi: 10.1371/journal.pone.0014504.
PubMed 21249218
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Long-Term Intravenous Nitrite Infusion in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT00103025
- Acronym / sponsor ID
- 050075
- Conditions
- Healthy
- Keywords
- Vasodilation, Hypotension, Hypertension, EDRF, Methemoglobinemia, Healthy Volunteer, HV
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- 4 Feb 2005
- Primary completion
- 10 May 2011 (actual)
- Study completion
- 10 May 2011 (actual)
- First posted
- 7 Feb 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will determine the dose of sodium nitrite that can safely be used to prevent constriction, or tightening, of the arteries. Narrowed arteries in the brain can cause stroke. Animal studies show that nitrite injections improve blood flow and that injections over long periods of time prevent damage to the arteries in the brain; however, there is no information on the effects of prolonged nitrite infusion in humans. This study will establish the safe dose and side effects of nitrite infusion in humans.
Healthy normal volunteers between 21 and 60 years of age may be eligible for this study. Candidates are screened for high or low blood pressure, aspirin use, pregnancy, and blood levels of nitrite and methemoglobin (a substance that temporarily and slightly lowers the oxygen carried in the red blood cells). Pregnant women are excluded from the study.
Participants are admitted to the Clinical Center for 16 1/4 days, the first 2 days in the hospital's intensive care unit (ICU). Upon admission they provide a medical history, have physical and cardiovascular examinations, and blood tests. For the infusion procedure, a catheter (thin plastic tube) is inserted into an artery in the wrist or the crease of the elbow to measure blood pressure, and catheters are placed in a vein in each arm for administering the nitrite and withdrawing blood samples.
In the morning of day 1, after initial blood pressure and heart rate measurements are taken and a blood sample is drawn, a saline (salt water) infusion is started. Blood pressure and heart rate are monitored every 30 minutes for 6 hours, then every hour for 6 hours, then every 2 hours for 12 hours. Blood samples are collected every 4 hours for 24 hours. On day 2, the sodium nitrite infusion begins. Blood pressure and methemoglobin are monitored every 10 minutes for the first 2 hours. If blood pressure remains stable, the frequency of measurements is decreased to every 30 minutes for 4 hours, then every 1 hour for the next 6 hours, and then every 4 hours for 12 hours. If the pressure continues to remain stable, monitoring continues every 8 hours for the rest of the study. Blood is drawn periodically from the catheter to determine the amount of nitrite and methemoglobin in the body, with decreasing frequency from several times during the first hour of the infusion to every 24 hours. After the first 24 to 48 hours of the nitrite infusion, participants are transferred from the ICU to a general nursing unit fo...
Detailed description
Nitric oxide (NO) is beneficial in treatment of many animal models of diseases like heart and brain ischemia, reperfusion injury, and delayed cerebral vasospasm after subarachnoid hemorrhage. It also has been shown to open blood-brain barrier facilitating transfer of chemotherapeutic agents, dilate constricted pulmonary arteries, and inhibit apoptosis, as well as modulate angiogenesis. Until recently, all these biological effects were attributed to the regional synthesis of nitric oxide by the endothelium and its local influence of vascular tone. However, "NO bioactivity" may be transported in blood and have biological effects at a distance from the site of entry into the circulation. These effects of NO are mediated by intravascular NO-stores. Candidates are protein and heme-bound NO species (RXNO) in plasma or erythrocytes and the oxidative NO-metabolite nitrite. Cumulating evidence suggests that nitrite may serve as a major intravascular storage pool for NO. Recent studies have shown that (1) regional, intra-arterial infusion of nitrite elicits a downstream vasodilator response in humans and (2) intravenous long-lasting administration prevents development of delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). These studies suggest a potential new therapeutic approach to many diseases. Despite extensive data documenting the pharmacokinetics and safety of the bolus and short intravascular infusions of nitrite, there are no human data evaluating safety and toxicity of prolonged delivery of nitrite, which would be required for treatment of vascular diseases.
OBJECTIVES
This study has the following objectives: (1) to determine the safety and (2) toxicity of a 48-hour and 14-day intravenous infusion of nitrite. The study should also help to elucidate the mechanism(s) through which nitrite ions contribute to vasodilation.
STUDY POPULATION
The study population will include sixteen 48-hour infusion healthy volunteers (out of 40 screened volunteers) of both genders, age 21-60, who will have a continuous intravenous infusion of sodium nitrite (the source of the drug will be determined by a CRADA).
DESIGN
This is a Phase I toxicity study of intermediate (48-hour) intravenous infusion of sodium nitrite in healthy volunteers.
OUTCOME MEASURES
Sixteen healthy volunteers of both genders, age 21-60, will have a 48-hour continuous intravenous infusion of sodium nitrite during which the subjects' clinical condition, blood levels of nitrite/methemoglobin, hematology, blood chemistry, and pressure will be meticulously monitored.
The first subject will receive the sodium nitrite infusion at 12 mg/48 hours. This dose, according to our knowledge from the former studies and detailed analysis of pharmacokinetics of sodium nitrite, will result in blood levels of sodium nitrite below 80 nmol/L, levels that are significantly below levels reported as normal (0.5 micromol/L to 1 micromol/L). Thus, we will use the modified accelerated titration design for Phase I Clinical studies. In the accelerated design the initial patient will start with the dose 1 nmol/min/kg/48hr, i.e. 12 mg total over 48 hours for a person weighting 60 kg. Cohorts of one new subject per dose level and double dose steps will be used during the initial accelerated stage. When the first instance of dose-limiting toxicity (DLT) is observed at any dose level, the next lower dose level cohort will be expanded to three patients and revert to the use of conventional modified Fibonacci escalation/de-escalation. If no DLT is observed at level 10, the cohort will be expanded to a total of three and de-escalated as appropriate. If no more than one subject among three patients experience DLT at this dose, level 10 will be considered to be the maximum tolerated dose (MTD).
The results of this 48-hour infusion phase 1 trial will be submitted to FDA before initiation of a 14-day clinical study.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Subjects must be 21-60 years of age.
- Subjects must be in good health.
- Subjects must provide informed, written consent for participation in this study.
- Female subjects of childbearing age must have a negative pregnancy test and agree to participate in assessment of menstrual cycle duration before, during, and after infusion.
- Subjects must be willing to temporarily stop any medications (except oral contraception), vitamin supplements, herbal medicines.
Key exclusion criteria (10 listed)
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 130 mg/dL), or diabetes mellitus (fasting blood glucose greater than 126 mg/dL).
- Subjects who have a history of smoking within two years.
- Subjects who have a history of cardiovascular disease, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- Subjects with red blood cell G6PD deficiency (levels below the lower limits of normal).
- Subjects with a history of reaction to a medication or other substance characterized by dyspnea and cyanosis.
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 Nitrite | Drug | – |
| Sodium Nitrite Injection | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 7782826Afshar JK, Pluta RM, Boock RJ, Thompson BG, Oldfield EH. Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg. 1995 Jul;83(1):118-22. doi: 10.3171/jns.1995.83.1.0118.
- Background: PubMed 14595407Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003 Dec;9(12):1498-505. doi: 10.1038/nm954. Epub 2003 Nov 2.
- Background: PubMed 6253831Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
- Derived from this study: PubMed 21249218Pluta RM, Oldfield EH, Bakhtian KD, Fathi AR, Smith RK, Devroom HL, Nahavandi M, Woo S, Figg WD, Lonser RR. Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers. PLoS One. 2011 Jan 10;6(1):e14504. doi: 10.1371/journal.pone.0014504.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Sodium Nitrite and Sodium Nitrite Injection in people with Healthy, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site 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 10 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 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00103025, which also lists 4 linked publications.
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 2 Jul 2017; AzTrials last refreshed its copy on 31 Oct 2026.