Nitrite Infusion in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 1

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 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.
    

Intervention name(s): Sodium Nitrite; Sodium Nitrite Injection
Intervention type(s): Drug; Drug
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Vasodilation; Hypotension; Hypertension; EDRF; Methemoglobinemia; Healthy Volunteer; HV