ObesityPhase 1NCT01122407
Pathophysiology of Cardiometabolic Risk Factors in African Americans
A Phase 1 study testing L-NMMA and Trimethaphan in people with Obesity and Hypertension, run by Vanderbilt University Medical Center at 1 site in United States.
Trial summary
The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women. Read more about this study
- Who is it for?
- Ages 30 to 50 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Obesity, Hypertension
- What is being tested?
- L-NMMA and Trimethaphan
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2010to Nov 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 30 to 50 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Race will be self-defined, but only subjects who report both parents of the same race will be included.
- All subjects will be pre-menopausal. Age 30-50 years old. We will recruit subjects with wide range of BMI 30-45 kg/m2. Both hypertensives and non-hypertensives will be recruited Hypertension will be defined as a seated blood pressure >130/85 determined in at least two occasions, and therefore, includes patients with "pre-hypertension".
- Subjects will be required to have a negative serum/urine pregnancy test. In addition, they will be asked to use a reliable contraceptive method prior to enrollment as determined by the PI (Dr. Cyndya Shibao)
Who cannot join
- Previous allergic reactions to any of the study medications (trimethaphan, L-NMMA, phenylephrine) or inability to take study medications as prescribed during the course of the study.
- Use of pacemaker or any metal implant NOT COMPATIBLE WITH MRI (artificial heart valves, implanted drug infusion ports, artificial limb, implanted nerve stimulator, metal pins, screws, plates, surgical staples).
- Type 1 or 2 diabetes mellitus as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication.
- Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy.
- History of smoking or current smokers. Significant weight change >5% from baseline in the past three months. Pregnancy or breast-feeding. History of serious neurological disease such as cerebral hemorrhage stroke, transient ischemic attack.
- History or presence of immunological or hematological disorders. Clinical significant gastrointestinal impairment that could interfere with drug absorption.
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- Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >1.5X upper limit of normal range).
- Impaired renal function (estimated glomerular filtration rate (eGFR) of <60mL/min).
- Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult.
- History of alcohol or drug abuse. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study.
- Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
About this study
Official title: Obesity, Hypertension in African American Women, Neuro-metabolic Mechanism
The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women. For this purpose we will use two non-FDA approved drugs:
Trimethaphan IND# 63826 Approval date 12/20/2001 L-NMMA IND# 41735 Approval date 09/1993
Read the detailed description
The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women.
Each year cardiovascular disease causes the deaths of approximately 54,000 African American women in the United States.Obesity, hypertension and insulin resistance are more prevalent among African American women as compared to men and Caucasians. These conditions put them at increased risk for the development of diabetes mellitus and cardiovascular disease.
Obesity is associated with increased sympathetic nervous system activity. A positive linear association has been consistently reported between body fat and muscle sympathetic nerve activity (MSNA), a direct measurement of baroreflex modulated vasoconstrictive sympathetic outflow. We and others have reported that in Caucasians this increased sympathetic activation contributes to obesity-associated hypertension. Our preliminary data in African American women indicates that for the same body mass index (BMI), African American women have lower autonomic contribution to blood pressure than Caucasians. We also found important differences in body composition with African American women having less fat mass. When total fat mass is analyzed based on its different components, visceral fat has shown to be a more metabolic active tissue than subcutaneous fat mass, and correlates with sympathetic activity better than any other indices of obesity. Therefore, in specific aim 1a, we propose to test the hypothesis that visceral fat mass modulates the contribution of the autonomic nervous system to blood pressure in obese African American women.
If the autonomic nervous system does not contribute to obesity-associated hypertension in African American women, then what causes these racial differences?. Other pathways involved in blood pressure regulation, such as nitric oxide, might be altered in this group. Several studies have reported that, compared to Caucasians, African Americans have decreased nitric oxide function in isolated vascular beds. The significance of these findings on blood pressure regulation is unknown. We have implemented in our laboratory, new approaches to isolate the contribution of nitric oxide (NO) to blood pressure, by blocking autonomic ganglia neurotransmission with trimethaphan and the production of NO with a nitric oxide synthase inhibitor. This paradigm allows us to define nitric oxide function in the absence of baroreflex buffering or interactions with the autonomic nervous system. In specific aim 1b, we propose to test the hypothesis that obese African American women have impaired NO contribution to blood pressure as part of the pathogenesis of hypertension in this group.
- Conditions
- Obesity, Hypertension
- Being tested
- L-NMMA, Trimethaphan
- Medical subject headings
- Obesity, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-NMMADrug
L-NMMA 250 ug/Kg/min
TrimethaphanDrug
Will infuse trimethaphan for until complete autonomic blockade is achieved.
| Study group | Role | What they receive |
|---|---|---|
| trimethaphan | Experimental | Trimethaphan infusion doses of 4 mg/min Receives: Drug: Trimethaphan |
| Trimethaphan plus L-NMMA | Experimental | Trimethaphan infusion 4 mg/min L-NMMA (L-NG-monomethyl Arginine citrate) infusion 250 mpg/kg/min A small group of arm 1 will receive both drugs. Receives: Drug: L-NMMA; Drug: Trimethaphan |
What is being measured
The primary outcome is the main question the study is designed to answer.
change in systolic blood pressure in response to trimethaphan, as a measurement of the tonic sympathetic contribution to blood pressure.
Will infuse trimethaphan for until complete autonomic blockade is achieved.
Measured: 30 minutes after initiation of Trimethaphan infusion
Secondary outcomes (1)
increase in systolic blood pressure induced by NOS inhibition with 250 ug/kg/min L-NMMA during autonomic withdrawal with trimethaphan.
After achieving complete autonomic blockade will infuse L-NMMA.
Measured: within 30 minutes
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2010 (estimated)
- Study startJan 2010
- Primary completionNov 2016
- Study completionNov 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for ObesityStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- 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 1
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Cyndya Shibao, Vanderbilt University Medical Center
- Investigators
- Cyndya Shibao, MD, Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01122407
- Sponsor's protocol ID
- 091282
- Other IDs
- K23HL103976-06
- Status last verified
- Jan 2017
- First submitted
- 10 May 2010
- Last updated
- 18 Jan 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Rahman S, Gamboa A, Saleem M, Kulapatana S, Diedrich A, Biaggioni I, Kirabo A, Shibao CA. Complete autonomic blockade reveals nitric oxide contribution to blood pressure regulation in obese Black women. Clin Auton Res. 2024 Aug;34(4):427-436. doi: 10.1007/s10286-024-01050-3. Epub 2024 Aug 1.
PubMed 39090323
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Obesity, Hypertension in African American Women, Neuro-metabolic Mechanism
- ClinicalTrials.gov ID
- NCT01122407
- Acronym / sponsor ID
- 091282
- Conditions
- Obesity, Hypertension
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Jan 2010
- Primary completion
- Nov 2016 (actual)
- Study completion
- Nov 2016 (actual)
- First posted
- 13 May 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women. For this purpose we will use two non-FDA approved drugs:
Trimethaphan IND# 63826 Approval date 12/20/2001 L-NMMA IND# 41735 Approval date 09/1993
Detailed description
The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women.
Each year cardiovascular disease causes the deaths of approximately 54,000 African American women in the United States.Obesity, hypertension and insulin resistance are more prevalent among African American women as compared to men and Caucasians. These conditions put them at increased risk for the development of diabetes mellitus and cardiovascular disease.
Obesity is associated with increased sympathetic nervous system activity. A positive linear association has been consistently reported between body fat and muscle sympathetic nerve activity (MSNA), a direct measurement of baroreflex modulated vasoconstrictive sympathetic outflow. We and others have reported that in Caucasians this increased sympathetic activation contributes to obesity-associated hypertension. Our preliminary data in African American women indicates that for the same body mass index (BMI), African American women have lower autonomic contribution to blood pressure than Caucasians. We also found important differences in body composition with African American women having less fat mass. When total fat mass is analyzed based on its different components, visceral fat has shown to be a more metabolic active tissue than subcutaneous fat mass, and correlates with sympathetic activity better than any other indices of obesity. Therefore, in specific aim 1a, we propose to test the hypothesis that visceral fat mass modulates the contribution of the autonomic nervous system to blood pressure in obese African American women.
If the autonomic nervous system does not contribute to obesity-associated hypertension in African American women, then what causes these racial differences?. Other pathways involved in blood pressure regulation, such as nitric oxide, might be altered in this group. Several studies have reported that, compared to Caucasians, African Americans have decreased nitric oxide function in isolated vascular beds. The significance of these findings on blood pressure regulation is unknown. We have implemented in our laboratory, new approaches to isolate the contribution of nitric oxide (NO) to blood pressure, by blocking autonomic ganglia neurotransmission with trimethaphan and the production of NO with a nitric oxide synthase inhibitor. This paradigm allows us to define nitric oxide function in the absence of baroreflex buffering or interactions with the autonomic nervous system. In specific aim 1b, we propose to test the hypothesis that obese African American women have impaired NO contribution to blood pressure as part of the pathogenesis of hypertension in this group.
Study design
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| trimethaphan | Experimental | Drug: TrimethaphanTrimethaphan infusion doses of 4 mg/min |
| Trimethaphan plus L-NMMA | Experimental | Drug: L-NMMA, Drug: TrimethaphanTrimethaphan infusion 4 mg/min L-NMMA (L-NG-monomethyl Arginine citrate) infusion 250 mpg/kg/min A small group of arm 1 will receive both drugs. |
Who may qualify
- Ages
- 30 to 50 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Race will be self-defined, but only subjects who report both parents of the same race will be included.
- All subjects will be pre-menopausal. Age 30-50 years old. We will recruit subjects with wide range of BMI 30-45 kg/m2. Both hypertensives and non-hypertensives will be recruited Hypertension will be defined as a seated blood pressure >130/85 determined in at least two occasions, and therefore, includes patients with "pre-hypertension".
- Subjects will be required to have a negative serum/urine pregnancy test. In addition, they will be asked to use a reliable contraceptive method prior to enrollment as determined by the PI (Dr. Cyndya Shibao)
Key exclusion criteria (11 listed)
- Previous allergic reactions to any of the study medications (trimethaphan, L-NMMA, phenylephrine) or inability to take study medications as prescribed during the course of the study.
- Use of pacemaker or any metal implant NOT COMPATIBLE WITH MRI (artificial heart valves, implanted drug infusion ports, artificial limb, implanted nerve stimulator, metal pins, screws, plates, surgical staples).
- Type 1 or 2 diabetes mellitus as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication.
- Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy.
- History of smoking or current smokers. Significant weight change >5% from baseline in the past three months. Pregnancy or breast-feeding. History of serious neurological disease such as cerebral hemorrhage stroke, transient ischemic attack.
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 |
|---|---|---|
| L-NMMAL-NMMA 250 ug/Kg/min | Drug | Trimethaphan plus L-NMMA |
| TrimethaphanWill infuse trimethaphan for until complete autonomic blockade is achieved. | Drug | Trimethaphan plus L-NMMA, trimethaphan |
Primary outcome
change in systolic blood pressure in response to trimethaphan, as a measurement of the tonic sympathetic contribution to blood pressure.
Time frame: 30 minutes after initiation of Trimethaphan infusion
Will infuse trimethaphan for until complete autonomic blockade is achieved.
1 secondary outcome
increase in systolic blood pressure induced by NOS inhibition with 250 ug/kg/min L-NMMA during autonomic withdrawal with trimethaphan.
Time frame: within 30 minutes
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2017.
- Derived from this study: PubMed 39090323Rahman S, Gamboa A, Saleem M, Kulapatana S, Diedrich A, Biaggioni I, Kirabo A, Shibao CA. Complete autonomic blockade reveals nitric oxide contribution to blood pressure regulation in obese Black women. Clin Auton Res. 2024 Aug;34(4):427-436. doi: 10.1007/s10286-024-01050-3. Epub 2024 Aug 1.
- Individual participant dataSharing planned: Undecided
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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.
Cyndya Shibao, MD principal investigator
Vanderbilt University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing L-NMMA and Trimethaphan in people with Obesity and Hypertension, run by Vanderbilt University Medical Center 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 3 inclusion and 11 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 18 Jan 2017. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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 systolic blood pressure in response to trimethaphan, as a measurement of the tonic sympathetic contribution to blood pressure. (time frame: 30 minutes after initiation of Trimethaphan infusion). 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 NCT01122407, 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 18 Jan 2017; AzTrials last refreshed its copy on 7 Nov 2026.