Vascular Dysfunction in Human Obesity Hypertension (VANISH)

Vascular Dysfunction in Human Obesity Hypertension: Integrative Role of Sympathetic and Renin-Angiotensin Systems

The purpose of the study is to test the effects of blocking sympathetic nerve activity with a drug called clonidine on blood vessel function and muscle nerve activity in adults who are obese and have high blood pressure.

The cohort of subjects will consist of 69 healthy young men and women age 18-79 years who are obese, defined as a body mass index > or = to 30 kg/m2, who have untreated systolic hypertension (systolic blood pressure > or = to 130 - <180 mmHg- average of at least 3 measurements 2 min apart after 10 min seated resting position). These 69 subjects will then be randomized to 3 treatment arms: clonidine (0.1 mg/day), hydrochlorothiazide (25 mg/day) or placebo for 4 weeks in years 1 and 2. All tablets will be encapsulated by to look identical. Subjects will randomly (1:1:1) receive one of the following combinations in a double-blind, placebo-controlled design:

1. Oral clonidine (0.1 mg twice/day)
2. Oral hydrochlorothiazide (12.5 mg twice/day)
3. Oral placebo

I

Study Overview

• Status: Terminated
• Conditions: Hypertension; Obesity; Prehypertension
• Intervention / Treatment: Drug: Placebo; Drug: Clonidine; Drug: Hydrochlorothiazide

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52240
      • University of Iowa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
• Systolic blood pressure >/= 130 mmHg and <180 mmHg
• Age is > or = 18 and < or = 79 years of age
• Weight stable (+/- 5 lbs) for the previous 3 months
• Healthy, as determined by health history questionnaire, blood chemistries, 12-lead ECG
• Blood chemistries indicative of normal renal (creatinine <2.0 mg/dl), liver (<3 times upper limit for ALT, AST), and thyroid function (TSH between 0.4 - 5.0 mU/L)
• If currently receiving treatment with or taking any of the following supplements, be willing and able to discontinue taking them for 2 weeks prior and throughout the treatment period: Vitamin C, E or other multivitamins containing vitamin C or E; or omega-3 fatty acids.
• No history of cardiovascular disease (e.g., heart attack, stroke, heart failure, valvular heart disease, cardiomyopathy), Type 1 or Type 2 diabetes, or peripheral arterial disease
• Non-smokers, defined as no history of smoking or no smoking for at least the past 1 year
• Normal resting 12-lead ECG (no evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter)

Exclusion Criteria:

• Systolic blood pressure >/=180 mmHg or diastolic blood pressure >110 mmHg
• History of cardiovascular disease such as heart angioplasty/stent or bypass surgery, myocardial infarction, stroke, heart failure with or without left ventricular ejection fraction <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart transplantation, Type 2 and Type 1 diabetes
• Smoking or history of smoking within past one year
• History of gastric ulcers, bleeding disorders, dyspepsia, severe gastroesophageal reflux disease (GERD), or metabolic acidosis
• History of chronic obstructive pulmonary disease (COPD)
• Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter)
• Serious neurologic disorders including seizures
• History of renal failure, dialysis or kidney transplant
• Serum creatinine > 2.0 mg/dL, or hepatic enzyme (ALT/AST) concentrations > 3 times the upper limit of normal
• History of HIV infection, hepatic cirrhosis, other preexisting liver disease, or positive HIV, Hepatitis B or C test at screening.
• Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
• History of recent chicken pox, shingles or influenza (ie., risk of Reye's syndrome)
• Recent flu-like symptoms within the past 2 weeks
• Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study. A urinary pregnancy test will be done on all females. If test is positive, the subject will be excluded.
• Women with history of hormone replacement therapy within the past 6 months
• History of rheumatoid arthritis, Grave's disease, systemic lupus erythematosis, and Wegener's granulomatosis;
• Taking lipid lowering (e.g., statins, niacin), glycemic control (e.g. metformin, insulin), anticoagulation, anti-seizure, anti-depression or antipsychotic agents
• History of co-morbid condition that would limit life expectancy to < 6 months.
• Taking chronic non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, indomethacin, naproxen, acetaminophen (Tylenol), ibuprofen (Advil, Motrin) and not able or willing to go off of for 2 weeks prior and during the study
• Taking cox-2 inhibitors (Celebrex, Vioxx, etc) or allopurinol (Zyloprim, Lopurin, Allopurin)
• Taking blood thinners such as coumadin (Warfarin), enoxaparin (Lovenox); clopidogrel (Plavix); dipyridamole (Persantine); heparin;
• Taking diabetic medications (Metformin, glyburide, insulin, etc.), thiazolidinediones (Avandia, Rezulin, Actos);
• Taking steroids or biologics : corticosteroids (prednisone); methotrexate, infliximab (Remicade), etanercept (Enbrel); anakinra;
• Taking thyroid medications such as levothyroxine (Levoxyl, Synthroid, Levoxyl, Unithroid); Levodopa;
• Taking Phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or Revatio®); PDE 3 inhibitors (e.g., cilostazol, milrinone, or vesnarinone); lithium
• May participate if no use of the following medications in the 48 hours prior to experimental visits: naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), other any non-steroidal anti-inflammatory drugs (NSAIDS)
• Vulnerable populations (prisoners, etc.)
• Any condition that, in the view of the PI, places the subject at high risk of poor treatment compliance or of not completing the study.
• History of alcohol abuse or >10 alcoholic units per week (1 unit= 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 oz alcohol)
• On weight loss drugs (e.g., Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanol-amine), or similar over-the-counter medications) within 3 months of screening
• Any surgery within 30 days of screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: Clonidine; Oral 0.2 mg/day (0.1 mg bid)for 4 weeks	Drug: Clonidine; Other Names: Catapress
Active Comparator: Hydrochlorothiazide; Oral, 12.5 mg/day qd, 4 weeks	Drug: Hydrochlorothiazide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aortic Stiffness	Carotid-femoral pulse wave velocity (PWV)	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24 Hour Average Systolic Blood Pressure	24 hour ambulatory systolic blood pressure	4 weeks

Collaborators and Investigators

• Sponsor: Gary L. Pierce
• Collaborators: American Heart Association

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: October 30, 2013
• First Submitted That Met QC Criteria: November 6, 2013
• First Posted (Estimate): November 14, 2013

Study Record Updates

• Last Update Posted (Actual): April 14, 2023
• Last Update Submitted That Met QC Criteria: March 26, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Prehypertension; Hypertension; Obese; Endothelial function; Sympathetic Nervous System; renin-angiotensin system
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hypertension; Obesity; Prehypertension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sympatholytics; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide; Clonidine
• Other Study ID Numbers: 201307779

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No