Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity
Primary Purpose
Obesity-Associated Insulin Resistance
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Moxonidine 0.2 MG
Amlodipine 5 MG
Sponsored by
About this trial
This is an interventional basic science trial for Obesity-Associated Insulin Resistance
Eligibility Criteria
Inclusion Criteria:
- Males and females of all races between 18 and 60 years of age
- Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg or currently on antihypertensive medication.
- Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2.
- Able and willing to provide informed consent.
Exclusion Criteria:
- Pregnancy or breast feeding
- Current smokers or history of heavy smoking (>2 packs/day)
- History of alcohol or drug abuse
- Previous allergic reaction to study medications
- Evidence of type I diabetes
- Cardiovascular disease other than hypertension
- History of serious cerebrovascular disease
- History or presence of immunological or hematological disorders
- Impaired renal function
- Treatment with any investigational drug in the 1 month preceding the study
- Inability to give, or withdraw, informed consent
- Other factors which in the investigator's opinion would prevent the subject from completing the protocol
Sites / Locations
- Vanderbilt UniversityRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Moxonidine
Amlodipine
Arm Description
Moxonidine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks
Amlodipine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks
Outcomes
Primary Outcome Measures
Insulin Sensitivity
Dose response curve to insulin ( measure as glucose infusion rate In mg/kg/min)
Secondary Outcome Measures
Full Information
NCT ID
NCT04329806
First Posted
March 16, 2020
Last Updated
September 24, 2023
Sponsor
Italo Biaggioni
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT04329806
Brief Title
Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity
Official Title
Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 23, 2021 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Italo Biaggioni
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to study the role of sympathetic mechanisms involved in chronic regulation of cardiovascular and metabolic abnormalities seen in obesity. The investigators will study the effects chronic sympathetic inhibition on insulin sensitivity, inflammation and endothelial function in obese hypertensive human subjects.
Detailed Description
Continuing Review (CR, 2021/08/04) Update: Removal of the angiotensin receptor blockade arm of the study
The presence of obesity increases the risk for hypertension and diabetes, in part due to the development of insulin resistance. Obesity is also associated with sympathetic activation and the overarching hypothesis is that sympathetic activation contributes to insulin resistance with impairment of its vascular and metabolic actions. Preliminary studies suggest that 1) Blood pressure can be normalized by autonomic blockade in obese hypertensives, 2) Sympathetic activation provides no metabolic benefit because the increase in resting energy expenditure associated with obesity is due to an increase in fat free mass rather than sympathetic activation. On the contrary, autonomic blockade: 3) Improves insulin sensitivity in obese hypertensives, 4) Reverses their impaired NO-mediated dilation, and 5) Reduces plasma isoprostanes, a measure of oxidative stress. Furthermore, these abnormalities are interrelated in negative feedback loops, whereby inflammation/oxidative stress impairs nitric oxide mechanisms, which in turn reduces insulin-mediated vasodilation important for substrate delivery, thus contributing to insulin resistance; insulin resistance leads to compensatory increases in insulin levels, which contributes to further sympathetic activation. Current treatment guidelines do not specifically address the treatment of obesity hypertension, and do not target sympathetic activation as a first line approach. It is important, therefore, to determine whether or not targeting sympathetic activation offers unique advantages in the treatment of obesity hypertension over current approaches. The investigators propose a proof-of-concept mechanistic study comparing the metabolic, vascular, and anti-inflammatory effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor blockade in obesity hypertension. The investigators will test the hypotheses that sympathetic activation contributes to 1) metabolic insulin resistance, which impairs the suppression of endogenous glucose production and the stimulation of glucose uptake normally provided by insulin, 2) vascular insulin resistance, which impairs insulin-mediated vasodilation and microvascular recruitment that normally promote glucose uptake, and 3) inflammation and oxidative stress, which contribute to insulin resistance and hypertension. The proposed studies will gauge the contribution of sympathetic activation to the cardiovascular and metabolic complications of obesity and provide the mechanistic insight to determine whether or not it should foster the efforts currently under way to develop novel therapies targeting sympathetic activation for hypertension.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity-Associated Insulin Resistance
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
72 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Moxonidine
Arm Type
Experimental
Arm Description
Moxonidine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks
Arm Title
Amlodipine
Arm Type
Active Comparator
Arm Description
Amlodipine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks
Intervention Type
Drug
Intervention Name(s)
Moxonidine 0.2 MG
Intervention Description
Moxonidine 0.2 MG twice daily
Intervention Type
Drug
Intervention Name(s)
Amlodipine 5 MG
Intervention Description
Amlodipine 5 MG twice daily
Primary Outcome Measure Information:
Title
Insulin Sensitivity
Description
Dose response curve to insulin ( measure as glucose infusion rate In mg/kg/min)
Time Frame
6 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Males and females of all races between 18 and 60 years of age
Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg or currently on antihypertensive medication.
Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2.
Able and willing to provide informed consent.
Exclusion Criteria:
Pregnancy or breast feeding
Current smokers or history of heavy smoking (>2 packs/day)
History of alcohol or drug abuse
Previous allergic reaction to study medications
Evidence of type I diabetes
Cardiovascular disease other than hypertension
History of serious cerebrovascular disease
History or presence of immunological or hematological disorders
Impaired renal function
Treatment with any investigational drug in the 1 month preceding the study
Inability to give, or withdraw, informed consent
Other factors which in the investigator's opinion would prevent the subject from completing the protocol
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Cynthia D Laws, MS,RHIA,CCRP
Phone
615-421-1994
Email
autonomicgroup@vumc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Alfredo Gamboa
Phone
615-875-1003
Email
alfredo.gamboa@vumc.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cynthia D Laws, MS, RHIA,ASQ-CQIA, CCRP
Phone
615-421-1994
Email
autonomicgroup@vumc.org
First Name & Middle Initial & Last Name & Degree
Emily C Smith, RN
Phone
615.875.1516
Email
autonomics@vumc.org
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, MD
First Name & Middle Initial & Last Name & Degree
Alfredo Gamboa, MD
First Name & Middle Initial & Last Name & Degree
Luis E Okamoto, MD
First Name & Middle Initial & Last Name & Degree
Cyndya A Shibao, MD
First Name & Middle Initial & Last Name & Degree
Andre Diedrich, MD/PhD
First Name & Middle Initial & Last Name & Degree
Emily C Smith
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity
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