Hypertension, Obesity, Prehypertension
Conditions
Keywords
Prehypertension, Hypertension, Obese, Sympathetic Nervous System, renin-angiotensin system, Endothelial function
Brief summary
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
Interventions
DRUGClonidine
DRUGHydrochlorothiazide
DRUGPlacebo
Sponsors
American Heart Association
Gary L. Pierce
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aortic Stiffness | 4 weeks | Carotid-femoral pulse wave velocity (PWV) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 24 Hour Average Systolic Blood Pressure | 4 weeks | 24 hour ambulatory systolic blood pressure |
Countries
United States
Participant flow
Pre-assignment details
Randomized to clonidine, HCTZ or placebo for 4 weeks
Participants by arm
| Arm | Count |
|---|---|
| Clonidine Oral 0.2 mg/day (0.1 mg bid)for 4 weeks
Clonidine | 11 |
| Hydrochlorothiazide Oral, 12.5 mg/day qd, 4 weeks
Hydrochlorothiazide | 11 |
| Placebo Placebo
Placebo | 11 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Clonidine | Hydrochlorothiazide | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 11 Participants | 10 Participants | 31 Participants |
| Age, Continuous | 41 years STANDARD_DEVIATION 18 | 31 years STANDARD_DEVIATION 10 | 37 years STANDARD_DEVIATION 19 | 35 years STANDARD_DEVIATION 16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 11 Participants | 10 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 10 Participants | 22 Participants |
| Region of Enrollment United States | 11 Participants | 11 Participants | 11 Participants | 33 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 6 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 10 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 1 / 10 | 0 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Aortic Stiffness
Carotid-femoral pulse wave velocity (PWV)
Time frame: 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clonidine | Aortic Stiffness | Baseline | 7.9 meters/sec | Standard Error 0.7 |
| Clonidine | Aortic Stiffness | 4 weeks | 7.3 meters/sec | Standard Error 0.6 |
| Hydrochlorothiazide | Aortic Stiffness | Baseline | 7.0 meters/sec | Standard Error 0.4 |
| Hydrochlorothiazide | Aortic Stiffness | 4 weeks | 7.0 meters/sec | Standard Error 0.3 |
| Placebo | Aortic Stiffness | Baseline | 8.1 meters/sec | Standard Error 1 |
| Placebo | Aortic Stiffness | 4 weeks | 8.0 meters/sec | Standard Error 1.2 |
Secondary
24 Hour Average Systolic Blood Pressure
24 hour ambulatory systolic blood pressure
Time frame: 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clonidine | 24 Hour Average Systolic Blood Pressure | Baseline | 133 mmHg | Standard Error 3 |
| Clonidine | 24 Hour Average Systolic Blood Pressure | 4 weeks | 126 mmHg | Standard Error 3 |
| Hydrochlorothiazide | 24 Hour Average Systolic Blood Pressure | Baseline | 135 mmHg | Standard Error 2 |
| Hydrochlorothiazide | 24 Hour Average Systolic Blood Pressure | 4 weeks | 131 mmHg | Standard Error 2 |
| Placebo | 24 Hour Average Systolic Blood Pressure | Baseline | 133 mmHg | Standard Error 2 |
| Placebo | 24 Hour Average Systolic Blood Pressure | 4 weeks | 134 mmHg | Standard Error 2 |