Ignite Creation Date:
2024-05-05 @ 11:41 AM
Last Modification Date:
2024-10-26 @ 9:11 AM
Study NCT ID:
NCT00103025
Status:
COMPLETED
Last Update Posted:
2017-07-02
First Post:
2005-02-05
Brief Title:
Nitrite Infusion in Healthy Volunteers
Sponsor:
National Institute of Neurological Disorders and Stroke NINDS
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Long-Term Intravenous Nitrite Infusion in Healthy Volunteers
Status:
COMPLETED
Status Verified Date:
2011-05-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 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 14 days the first 2 days in the hospitals 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
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 14 days the first 2 days in the hospitals 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 mechanisms 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 nitritemethemoglobin hematology blood chemistry and pressure will be meticulously monitored
The first subject will receive the sodium nitrite infusion at 12 mg48 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 nmolL levels that are significantly below levels reported as normal 05 micromolL to 1 micromolL 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 nmolminkg48hr ie 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 escalationde-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
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 mechanisms 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 nitritemethemoglobin hematology blood chemistry and pressure will be meticulously monitored
The first subject will receive the sodium nitrite infusion at 12 mg48 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 nmolL levels that are significantly below levels reported as normal 05 micromolL to 1 micromolL 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 nmolminkg48hr ie 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 escalationde-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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05-N-0075 | None | None | None |