Mitigating the Pro-inflammatory Phenotype of Obesity

Study Overview
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Brief Summary
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The purpose of this study is to examine the hypothesize that 4 weeks of sympathetic nerve activity (SNA) inhibition (oral clonidine) will cause a significant reduction in circulating blood concentrations and endothelial cell expression of inflammatory markers (e.g., TNF-α, IL-6). Our study is a prospective study using a randomized, double-blinded design to test 4 weeks of SNA blockade (oral clonidine) compared with a BP-lowering control condition (diuretic, hydrochlorothiazide) or a placebo.

Detailed Description
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Using a randomized, double-blinded, parallel-design approach, we hypothesize that 4 weeks of SNA blockade (oral clonidine) will cause a significant reduction in expression of inflammatory markers in blood, endothelial cells, and central adipose compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment. Determine the extent to which inflammation in the body is caused by elevated sympathetic nerve activity

Official Title
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Mitigating the Pro-inflammatory Phenotype of Obesity

Conditions
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Blood Pressure, Diabetes, Obesity, Insulin Resistance, Diuretics Drug Reactions, Sympathetic Nerve Activity

Intervention / Treatment
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* Drug: Hydrochlorothiazide 12.5Mg Tab
* Drug: Clonidine Pill
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female, age 18-79 Obese: BMI > 30 m/kg2 Hypertensive: blood pressure >130/80 Elevated insulin resistance (HOMA-IR > 2.5) Waist circ: >102 cm (men) and >88 cm (women) Fasting glucose < 126 mg/dL Fasting triglycerides < 250 mg/dL HbA1c < 6.5% Willing to visit research lab (Fairway CTSU) Willing to undergo a blood draw Able to provide written informed consent Exclusion Criteria: Current use of clonidine or beta-blockers Current smoker or History of smoking in the past 3 months. Hyperlipidemia: Fasting triglycerides > 250 mg/dL Currently taking hypertension medication History of heart disease (e.g., myocardial infarction, stent, byass, heart attack, stroke, heart failure, valvular heart disease, cardiomyopathy) History of neurological disorders History of transplant Actively participating in other studies, except for a registry study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Mixed Model ANOVA 3-way analysis of variance to assess pain and BP responses to the clonidine, diuretic vs. placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>KU Investigational Pharmacy will provide the drug prescription bottle with 35-day supply of placebo to the research coordinator to give to the research participant. The placebo is an inert substance with no intended medical value and is used as a negative control for comparison with the study drug. Participants will receive a Placebo Pill; has no active ingredients but is made to look like the study drug. | Drug: Placebo<br>* Will receive a 4 week supply (35 days) of Placebo Pills; has no active ingredients but is made to look like the study drug.<br>|
| Experimental: Clonidine<br>KU Investigational Pharmacy will provide the drug prescription bottle with 35-day supply of clonidine to the research coordinator to give to the research participant. Planned use in this study Condition/disease indication(s): Vascular function and blood flow Subject population: Hypertension Dose(s): 0.1 mg (oral) Administration: Oral Dosing regimen: 0.1 mg twice daily by mouth | Drug: Clonidine Pill<br>* Will receive 4 week supply (35 days) of Clonidine Pills (0.1 mg twice/day) Planned use in this study Condition/disease indication(s): Vascular function and blood flow Subject population: Hypertension Dose(s): 0.1 mg (oral) Administration: Oral Dosing regimen: 0.1 mg twice daily by mouth<br>* Other names: Clonidine;|
| Experimental: Hydrochlorothiazide (HCTZ)<br>KU Investigational Pharmacy will provide the drug prescription bottle with 35-day supply of Hydrochlorothiazide to the research coordinator to give to the research participant. Planned use in this study Condition/disease indication(s): Hypertension Subject population: Hypertension Dose(s): 25 mg/day Administration: Oral Dosing regimen: 12.5 mg twice per day | Drug: Hydrochlorothiazide 12.5Mg Tab<br>* Will receive 4 week supply (35 days) of Hydrochlorothiazide Pills (12.5 mg twice a day) Planned use in this study Condition/disease indication(s): Hypertension Subject population: Hypertension Dose(s): 25 mg/day Administration: Oral Dosing regimen: 12.5 mg twice per day<br>* Other names: Hydrochlorothiazide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Work: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | Difference in inflammatory markers in blood compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment Norepinephrine (inflammation) Blood Test: pg/mL normal range for norepinephrine is 70 to 1700 pg/mL Tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL6) Blood Test: pg/mL normal values: IL-6 was 6-31 pg/mL and TNF-α 5 pg/mL, Nitrotyrosine (Oxidative stress) | Baseline | 
| Endothelial Cell Sample: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | Difference in endothelial cells samples compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment Endothelial cell tissue will be assessed by the KU Histology Core for markers of inflammation and oxidative stress independently from the PI's lab, | Baseline | 
| Adipose Tissue Sample: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | Difference in central adipose compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment Adipose tissue are expected following 4 weeks of clonidine but not HCTZ or placebo | Baseline | 
| Blood Work: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | The difference in electrolytes blood test of participants in the Clonidine group compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment. • Blood Test: Electrolyte check by examining potassium concentration in blood. If potassium is 3.5 millimoles per liter or lower, oral 10 mg KCL will be prescribed to subject by a physician. | 1 Week | 
| Blood Work: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | The difference in electrolytes blood test of participants in the Clonidine group compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment. • Blood Test: Electrolyte check by examining potassium concentration in blood. If potassium is 3.5 millimoles per liter or lower, oral 10 mg KCL will be prescribed to subject by a physician. | 2 Week | 
| Blood Work: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | Difference in inflammatory markers in blood, endothelial cells, and central adipose compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment Norepinephrine (inflammation) Blood Test: pg/mL normal range for norepinephrine is 70 to 1700 pg/mL Tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL6) Blood Test: pg/mL normal values: IL-6 was 6-31 pg/mL and TNF-α 5 pg/mL, Nitrotyrosine (Oxidative stress) | 4 Week | 
| Endothelial Cell Sample: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | Difference in endothelial cells samples compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment Endothelial cell tissue will be assessed by the KU Histology Core for markers of inflammation and oxidative stress independently from the PI's lab, | 4 Week | 
| Adipose Tissue Sample: Efficacy of 4-week supply of Clonidine Compared VS 4-week supply of control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment | Difference in central adipose compared with a BP-lowering control condition using hydrochlorothiazide (HCTZ) and a separate placebo treatment Adipose tissue are expected following 4 weeks of clonidine but not HCTZ or placebo | 4 Week |