A Phase 2 interventional study of 14Nitrogen Sodium Nitrite in Metabolic Syndrome and Hypertension, sponsored by Gladwin, Mark, MD. Completed at 1 site in United States. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2019-04-16.
Sponsored by Gladwin, Mark, MD · Phase 2, Interventional, and Treatment
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.
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.
6,689 studies on the registry are indexed under Hypertension; 965 are open to participants now.
This study's enrollment of 20 is below the median of 90 across 4,995 interventional studies indexed under Hypertension.
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sodium nitrite 40 mg three times a day for 12 weeks
Drug: 14Nitrogen Sodium Nitrite
oral formulation of sodium nitrite 40 mg three times a day for 12 weeks
Also known as: sodium nitrite
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.
Time frame: measured at 0 (baseline) and at 12 weeks
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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
Subjects 18-60 years with metabolic syndrome and hypertension were recruited through the University of Pittsburgh Research Participant Registry, University of Pittsburgh Nutrition and Obesity Research Center Registry, university and University of Pittsburgh Medical Center hospital electronic and paper advertising, and radio and bus advertising.
| Milestone | 14Nitrogen Sodium Nitrite |
|---|---|
| Started | 20 |
| Completed | 20 |
| Not completed | 0 |
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.
| mg/kg lean body mass/minute | 14Nitrogen Sodium Nitrite |
|---|---|
| Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period | 0.76 ± 0.58 |
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.
| mmHg | 14Nitrogen Sodium Nitrite |
|---|---|
| Peak Change in Systolic Blood Pressure Over 12 Week Study Period | -10.45 ± 3.01 |
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.
| mmHg | 14Nitrogen Sodium Nitrite |
|---|---|
| Peak Change in Diastolic Blood Pressure Over 12 Week Study Period | -13.05 ± 2.2 |
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.
| mmHg | 14Nitrogen Sodium Nitrite |
|---|---|
| Peak Change in Mean Arterial Pressure Over 12 Week Study Period | -12.00 ± 2.15 |
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).
| percentage of total hemoglobin | 14Nitrogen Sodium Nitrite |
|---|---|
| Peak Change in Methemoglobin Over 12 Week Study Period | 0.42 ± 0.11 |
Collected over Adverse event (AE) collection occurred throughout 12 weeks of study drug treatment until 1 month after completing study drug.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 14Nitrogen Sodium Nitrite | 0/20 (0%) | 0/20 (0%) | 20/20 (100%) |
| Event | 14Nitrogen Sodium Nitrite |
|---|---|
| HeadacheNervous system disorders | 15/20 |
| NauseaGastrointestinal disorders | 9/20 |
| Upper respiratory symptomsRespiratory, thoracic and mediastinal disorders | 9/20 |
| Dry mouthSkin and subcutaneous tissue disorders | 6/20 |
| DizzinessNervous system disorders | 5/20 |
| FlushingVascular disorders | 5/20 |
| Back painMusculoskeletal and connective tissue disorders | 5/20 |
| Abdominal painGastrointestinal disorders | 4/20 |
| VomitingGastrointestinal disorders | 4/20 |
| Joint painMusculoskeletal and connective tissue disorders | 4/20 |
Participants completing sodium nitrite 40 mg three times a day for 12 weeks
| Age, Continuous(years) | 14Nitrogen Sodium Nitrite |
|---|---|
| Mean | 52.4 (39 to 59) |
| Sex: Female, Male(Participants) | 14Nitrogen Sodium Nitrite |
|---|---|
| Female | 15 |
| Male | 5 |
| Race (NIH/OMB)(Participants) | 14Nitrogen Sodium Nitrite |
|---|---|
| American Indian or Alaska Native | 2 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 6 |
| White | 12 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | 14Nitrogen Sodium Nitrite |
|---|---|
| United States | 20 |
| Systolic blood pressure (SBP)(mmHg) | 14Nitrogen Sodium Nitrite |
|---|---|
| Mean | 146 ± 15.7 |
| Diastolic blood pressure (DBP)(mmHg) | 14Nitrogen Sodium Nitrite |
|---|---|
| Mean | 87.8 ± 8.57 |
| Mean arterial pressure (MAP)(mmHg) | 14Nitrogen Sodium Nitrite |
|---|---|
| Mean | 109 ± 11.1 |
| Body mass index (BMI)(kg/m^2) | 14Nitrogen Sodium Nitrite |
|---|---|
| Mean | 40.8 ± 6.63 |
4 further baseline measures are reported on the registry.
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Gladwin, Mark, MD