Clinical trial NCT01681810: Oral Nitrite in Adults With Metabolic Syndrome and Hypertension
Official title: An Open-Label Study of Oral Nitrite in Adults With Metabolic Syndrome and Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metabolic Syndrome
Hypertension
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2012-09-10
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period
timeFrame: measured at 0 (baseline) and at 12 weeks
Secondary outcomes:
measure: Peak Change in Systolic Blood Pressure Over 12 Week Study Period
timeFrame: measured at 0 (baseline) and bi-weekly over 12 weeks
measure: Peak Change in Diastolic Blood Pressure Over 12 Week Study Period
timeFrame: measured at 0 (baseline) and bi-weekly over 12 weeks
measure: Peak Change in Mean Arterial Pressure Over 12 Week Study Period
timeFrame: measured at 0 (baseline) and bi-weekly over 12 weeks
measure: Peak Change in Methemoglobin Over 12 Week Study Period
timeFrame: measured at 0 (baseline) and bi-weekly over 12 weeks
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Montefiore Hospital of University of Pittsburgh Medical Center (UPMC)
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Kara S Hughan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Mark Gladwin, MD
role: STUDY_DIRECTOR
References:
citation: Hughan KS, Levine A, Helbling N, Anthony S, DeLany JP, Stefanovic-Racic M, Goodpaster BH, Gladwin MT. Effects of Oral Sodium Nitrite on Blood Pressure, Insulin Sensitivity, and Intima-Media Arterial Thickening in Adults With Hypertension and Metabolic Syndrome. Hypertension. 2020 Sep;76(3):866-874. doi: 10.1161/HYPERTENSIONAHA.120.14930. Epub 2020 Aug 3.