Oral Nitrite Trial for Hypertension and Metabolic Syndrome

Phase 2

Withdrawn

• Conditions: Metabolic Syndrome; Hypertension
• Interventions: Drug: 14 Nitrogen (N) Sodium Nitrite; Drug: Placebo

• Registration Number: NCT02517697
• Lead Sponsor: Gladwin, Mark, MD

Brief Summary

The objective of the study is to investigate effects of inorganic sodium nitrite on the cardiometabolic and hormonal disturbances observed in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction.

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. Nitrite could then be 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 will investigate the inorganic nitrite effects (in any form) on insulin sensitivity in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction. This will be the third human trial using orally delivered nitrite (previously as aqueous solution).

Study Timeline

• Study First Submitted: 2015-08-05
• Study First Submitted QC: 2015-08-05
• Study First Posted: 2015-08-07
• Study Start: 2020-10
• Status Verified: 2021-04
• Primary Completion: 2021-04-13
• Study Completion: 2021-04-13
• Last Update Submitted: 2021-04-13
• Last Update Posted: 2021-04-19

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Age 18-60 years
• Body mass index (BMI) ≥ 30 kg/m2
• Hypertension: defined as systolic blood pressure ≥130 and/or diastolic blood pressure ≥85 mm Hg
• Waist circumference: >102 cm in men, >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), Intra Uterine Device (IUD), DepoProvera shot)
• Current use of ≥3 anti-hypertensive agents regardless of blood pressure control or normotensive on a single or double agent
• Current use of phosphodiesterase-5 (PD) inhibitors or organic nitrates. We will not exclude for dietary sources of nitrate/nitrite.
• 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) >8 milli-International unit/mL
• Smoker
• Anemia (central lab hemoglobin < 11g/dL)
• Active periodontal disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active drug	14 Nitrogen (N) Sodium Nitrite	14 Nitrogen (N) Sodium Nitrite 40mg three times daily (TID)
Placebo	Placebo	placebo capsules three time daily (TID)

Primary Outcome Measures

Name	Time	Method
Change in insulin sensitivity (i.e. insulin stimulated glucose disposal)	baseline and 12 weeks	obtained by hyperinsulinemic euglycemic clamp

Secondary Outcome Measures

Name	Time	Method
Change in systolic blood pressure	baseline and 12 weeks	ambulatory blood pressure
Change in mean arterial pressure	baseline and then biweekly throughout the 12 week treatment	ambulatory blood pressure
Change in diastolic blood pressure	baseline and 12 weeks	ambulatory blood pressure
Change in methemoglobin level	baseline and then biweekly throughout the 12 week treatment	by co-oximetry

Trial Locations

Locations (1)

Montefiore Hospital of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States