Metabolic SyndromePhase 2ONTXNCT01681810

Oral Nitrite in Adults With Metabolic Syndrome and Hypertension

A Phase 2 study testing 14Nitrogen Sodium Nitrite in people with Metabolic Syndrome and Hypertension, run by Gladwin, Mark, MD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial 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. Read more about this study

Who is it for?: Ages 18 to 60 years
Conditions the study is for: Metabolic Syndrome, Hypertension
What is being tested?: 14Nitrogen Sodium Nitrite
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 20 participants
Where: 1 siteUnited States
Study dates: Oct 2012to 8 Mar 2018
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 60 years
All sexes
No healthy volunteers
Adult

Who may be able to join

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

Who cannot join

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.

Show all 10Show fewer

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)

Trial locations and contacts

1 site in 1 country.

United States1 site

Montefiore Hospital of University of Pittsburgh Medical Center (UPMC)
Pittsburgh, Pennsylvania, 15213

Other trials in United States

About this study

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

Read the 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.

Conditions: Metabolic Syndrome, Hypertension
Being tested: 14Nitrogen Sodium Nitrite
Medical subject headings: Metabolic Syndrome, Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

14Nitrogen Sodium NitriteDrug
Also called sodium nitrite
oral formulation of sodium nitrite 40 mg three times a day for 12 weeks

Study groups in NCT01681810
Study group	Role	What they receive
14Nitrogen sodium nitrite	Experimental	sodium nitrite 40 mg three times a day for 12 weeks Receives: Drug: 14Nitrogen Sodium Nitrite

What is being measured

The primary outcome is the main question the study is designed to answer.

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: measured at 0 (baseline) and at 12 weeks

Secondary outcomes (4)

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: 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: 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: 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: measured at 0 (baseline) and bi-weekly over 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Oct 20128 Mar 2018

First posted10 Sep 2012 (estimated)
Study startOct 2012
Primary completion8 Feb 2018
Study completion8 Mar 2018

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Metabolic SyndromeStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 20 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01681810
Sponsor's protocol ID: PRO11030131
Acronym: ONTX
Status last verified: Mar 2019
First submitted: 3 Jul 2012
Last updated: 16 Apr 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Publications

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.
PubMed 32755471

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingObservational study
Defining the Natural History of Squamous Cell Carcinoma in Fanconi Anemia
Fanconi Anemia, Inherited Bone Marrow Failure Syndrome
Not yet recruitingPhase 2
Osilodrostat for Glycemic Control in Mild Autonomous Cortisol Secretion (MACS) With Difficult-To-Control Type 2 Diabetes - A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study
Mild Autonomous Cortisol Secretion (MACS), Diabetes Mellitus (Type 2)
Active, not recruiting
Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
Neuromuscular Diseases (NMD), Amyotrophic Lateral Sclerosis
Not yet recruitingObservational study
Clinical Genetics Branch Eligibility Screening Survey
Melanoma, Li-Fraumeni Syndrome
Not yet recruitingPhase 2
Effects of Meal Macronutrients on Postprandial Lipids
Nephrotic Syndrome, Lipodystrophy

All Metabolic Syndrome trials

Study at a glance

From the registry record, last updated by the sponsor on 16 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: An Open-Label Study of Oral Nitrite in Adults With Metabolic Syndrome and Hypertension
ClinicalTrials.gov ID: NCT01681810
Acronym / sponsor ID: ONTX / PRO11030131
Conditions: Metabolic Syndrome, Hypertension
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 20 participants (actual)
Lead sponsor: Gladwin, Mark, MD
Study start: Oct 2012
Primary completion: 8 Feb 2018 (actual)
Study completion: 8 Mar 2018 (actual)
First posted: 10 Sep 2012 (estimated)
Results: Posted 16 Apr 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
14Nitrogen sodium nitrite	Experimental	Drug: 14Nitrogen Sodium Nitritesodium nitrite 40 mg three times a day for 12 weeks

Who may qualify

Ages: 18 to 60 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult

Key inclusion criteria (4 listed)

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

Key exclusion criteria (10 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
14Nitrogen Sodium NitriteAlso: sodium nitriteoral formulation of sodium nitrite 40 mg three times a day for 12 weeks	Drug	14Nitrogen sodium nitrite

Primary outcome

Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period
Time frame: measured at 0 (baseline) and at 12 weeks
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.

4 secondary outcomes

Peak Change in Systolic Blood Pressure Over 12 Week Study Period
Time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
Peak Change in Diastolic Blood Pressure Over 12 Week Study Period
Time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
Peak Change in Mean Arterial Pressure Over 12 Week Study Period
Time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
Peak Change in Methemoglobin Over 12 Week Study Period
Time frame: measured at 0 (baseline) and bi-weekly over 12 weeks

Results and safety

Results posted to the registry on 16 Apr 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
14Nitrogen Sodium Nitrite	20	20

Primary outcome: Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period

Time frame: measured at 0 (baseline) and at 12 weeks. Mean (Standard Error). Unit: mg/kg lean body mass/minute

Measure	14Nitrogen Sodium Nitrite n = 19
Value	0.76 (0.58)

14Nitrogen Sodium Nitrite: p = 0.2068, t-test, 2 sided

Population analysed: The pre-drug hyperinsulinemic euglycemic clamp isotope data for 1 subject (used to determine insulin stimulated glucose disposal) was not interpretable despite repeat of the mass spectrometry assay. Therefore, the pre- and post- outcome measure for this subject was removed from analysis, giving a n=19 sample size for this analysis.

4 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event (AE) collection occurred throughout 12 weeks of study drug treatment until 1 month after completing study drug.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
14Nitrogen Sodium Nitrite	0 of 20 (0%)	20 of 20 (100%)	0 of 20

Limitations and caveats (from the sponsor): The pre-drug clamp isotope data for 1 subject (used to determine insulin stimulated glucose disposal) was uninterpretable, despite repeating the mass spectrometry assay. Subject's isotope data was removed from analysis (n=19 analysis sample size).

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32755471Hughan 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.

Related trials for Metabolic Syndrome

RecruitingObservational study
Defining the Natural History of Squamous Cell Carcinoma in Fanconi Anemia
Fanconi Anemia, Inherited Bone Marrow Failure Syndrome
Not yet recruitingPhase 2
Osilodrostat for Glycemic Control in Mild Autonomous Cortisol Secretion (MACS) With Difficult-To-Control Type 2 Diabetes - A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study
Mild Autonomous Cortisol Secretion (MACS), Diabetes Mellitus (Type 2)
Active, not recruiting
Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
Neuromuscular Diseases (NMD), Amyotrophic Lateral Sclerosis
Not yet recruitingObservational study
Clinical Genetics Branch Eligibility Screening Survey
Melanoma, Li-Fraumeni Syndrome
Not yet recruitingPhase 2
Effects of Meal Macronutrients on Postprandial Lipids
Nephrotic Syndrome, Lipodystrophy

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Kara S Hughan, MD principal investigator

University of Pittsburgh

Mark Gladwin, MD study director

University of Pittsburgh

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 14Nitrogen Sodium Nitrite in people with Metabolic Syndrome and Hypertension, run by Gladwin, Mark, MD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period (time frame: measured at 0 (baseline) and at 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01681810, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Apr 2019.