Oral Nitrite in Adults With Metabolic Syndrome and Hypertension

Study Overview
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Brief Summary
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This research study is being conducted to examine the effects of daily inorganic nitrite treatment on the cardiometabolic and hormonal disturbances observed in overweight/obese adults with the metabolic syndrome and high blood pressure. Ultimately, oral nitrite therapy may have a major impact on the prevention and treatment of both diabetes and cardiovascular disease.

Detailed Description
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Cardiovascular disease remains the leading cause of death in the United States and worldwide. Several studies have demonstrated that fruit and vegetable rich diets significantly reduced blood pressure and reduced the risk of ischemic stroke and cardiovascular disease in general, the exact mechanisms remain poorly understood. Preclinical and clinical research over the last decade has revealed the important vasoprotective effects of nitrates and nitrites with regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction. More recent findings suggest that inorganic nitrate and nitrite therapy may be involved in the regulation of glucose-insulin homeostasis. For this reason, development of an oral formulation of nitrite salt represents a rational avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would ensure rapid acting effects upon absorption which can be further oxidized to nitrate via the enterosalivary circulation pathway. In this pathway, about 25% of circulating nitrate is concentrated in the saliva and reduced to nitrite by commensal mouth bacteria with nitrate reductase enzymes. The proposal is the first human study to investigate the inorganic nitrite effects (in any form) on insulin sensitivity in a patient population. This is the second human trial using orally delivered nitrite (previously as aqueous solution). In the initial phase of the study, step up dosing and frequency of oral sodium nitrite to 40 mg three times daily occurred with no serious adverse events. After three subjects completed the study intervention on sodium nitrite 20 mg three times daily for 2 weeks followed by 40 mg three times daily for the remaining 10 weeks with no serious adverse events, all subjects in this current phase of the trial (n=20) began the 12-week study intervention with 40 mg three times daily. At the same time, in person monitoring visits (which included brief physical exams, directly observed nitrite dosing, secondary outcome measure assessment of methemoglobin level and blood pressure, interval histories, medication compliance review, symptom review and dispensing of study drug) were spaced from weekly intervals to subjects alternating weekly in person visits with phone visits.

Official Title
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An Open-Label Study of Oral Nitrite in Adults With Metabolic Syndrome and Hypertension

Conditions
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Metabolic Syndrome, Hypertension

Intervention / Treatment
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* Drug: 14Nitrogen Sodium Nitrite


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-60 years Body mass index (BMI) greater than or equal to 30 kg/m^2 Hypertension: defined as systolic blood pressure (SBP) greater than or equal to 130 and/or diastolic blood pressure (DBP) greater than or equal to 85 mm Hg Waist circumference: greater than 102 cm in men, greater than 88 cm in women Exclusion Criteria: Positive urine pregnancy test or breastfeeding Concurrent use of medications affecting glucose metabolism (oral hypoglycemics, insulin, atypical antipsychotics) Recent addition or change in dosing of hormonal contraceptive medications [oral contraceptive pill (OCP), intrauterine device (IUD), DepoProvera] Current use of greater than or equal to 3 anti-hypertensive agents regardless of blood pressure control or normotensive on a single or double agent Current use of phosphodiesterase-5 inhibitors or organic nitrates Not stable on treatments for the prior three months or not planning to remain on current dose of medications for blood pressure, contraception, etc. Known chronic psychiatric or medical conditions including diabetes, liver or kidney disease or obesity syndromes Thyroid-stimulating hormone (TSH) greater than 8 milli-International unit/mL Smoker Anemia (central lab hemoglobin less than 11g/dL)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 14Nitrogen sodium nitrite<br>sodium nitrite 40 mg three times a day for 12 weeks | Drug: 14Nitrogen Sodium Nitrite<br>* oral formulation of sodium nitrite 40 mg three times a day for 12 weeks<br>* Other names: sodium nitrite;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period | Change in insulin stimulated glucose disposal was assessed during the 4-hour hyperinsulinemic euglycemic clamp at end of the 12 weeks and was compared to baseline (pre-nitrite). Insulin stimulated glucose disposal (mg/min) was calculated in the final 20 minutes of the 4-hour clamp at steady state and expressed as mg per kg lean body mass (as measured by DEXA) per minute. HumuLIN R regular insulin was infused at a rate of 40 microUnits/m2/min. A non-radioactive glucose isotope dilution (Isotec, Inc) was delivered as a primed, then constant infusion of the 98+% enriched stable isotope of D-glucose [6,6-D2] (0.22 umol x kg-1, 17.6 umol x kg-1 prime). Plasma glucose was clamped between 85-95 mg/dL with a variable infusion of 20% dextrose in water. The rate of dextrose infusion was adjusted based on arterialized plasma glucose measurements obtained every 5 minutes. | measured at 0 (baseline) and at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Change in Systolic Blood Pressure Over 12 Week Study Period | Peak change in systolic blood pressure (SBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 SBP measurements were averaged. | measured at 0 (baseline) and bi-weekly over 12 weeks | 
| Peak Change in Diastolic Blood Pressure Over 12 Week Study Period | Peak change in diastolic blood pressure (DBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 DBP measurements were averaged. | measured at 0 (baseline) and bi-weekly over 12 weeks | 
| Peak Change in Mean Arterial Pressure Over 12 Week Study Period | Peak change in mean arterial pressure (MAP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 MAP measurements were averaged. | measured at 0 (baseline) and bi-weekly over 12 weeks | 
| Peak Change in Methemoglobin Over 12 Week Study Period | Peak change in methemoglobin on sodium nitrite compared to baseline. Methemoglobin was assessed bi-weekly at study visits 30 minutes after directly observed nitrite dosing using noninvasive co-oximetry (Masimo Corp, Irvine, CA). | measured at 0 (baseline) and bi-weekly over 12 weeks |