Conditions: Hypertension
Keywords: Hypertension blood pressure Aldosterone Eplerenone Amlodipine Primary aldosteronism Exercise pressor reflex handgrip exercise passive arm cycling active arm cycling
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 14
Healthy volunteers: yes

Brief summary:
Hypertensive patients often show an exaggerated rise in blood pressure during exercise through overactivity of the exercise pressor reflex. An increasing body of evidence suggests a role for aldosterone in augmenting the exercise pressor reflex in hypertensive humans. We hypothesize that this effect of aldosterone is mediated by its direct action on the central nervous system and that administration of mineralocorticoid receptor antagonists constitute an effective treatment for EPR overactivity in hypertension, independent of reductions in resting BP.

Detailed description:
Hypertensive patients are known to display exaggerated rise in blood pressure (BP) during exercise but the underlying mechanisms are poorly understood.

Traditionally, muscle afferents were dichotomized as metaboreceptors, which are activated slowly and only during intense or ischemic muscle contraction, or mechanoreceptors, which respond quickly to even mild deformation of their receptive fields. The increase in sympathetic nerve activity and BP caused by activation of these receptors, known as exercise pressor reflex, is normally buffered by activation arterial baroreceptors, which are reset to operate at higher BP range but at the same level of sensitivity. Mechanisms responsible for overactive exercise pressor reflex in hypertension remain unknown, but an increasing body of evidence suggested a role for aldosterone in regulating resting central sympathetic outflow in both hypertensive rats and humans.

Experiments will be performed on 3 groups of subjects 1) stage I (140-159/90-99 mmHg) subjects with essential hypertension, 2) stage I hypertensive subjects with Primary Aldosteronism (PA), and 3) normotensive controls. All participants will attend a baseline study visit, which will include a physical examination, a medical history review, vital sign measurements, and blood and urine collection. Small electrodes will be used to measure muscle nerve activity while the subjects perform a series of exercises that include passive arm cycling, active arm cycling, rhythmic hand grip, sustained hand grip and cold pressor test. Muscle blood flow will be measured before and after hand grip exercises.

A subgroup of subjects with essential hypertension and PA will be assigned to receive Eplerenone or Amlodipine on a randomized, double-blinded design. Participants will attend two weeks visits over a period of 16 weeks. Study visits include measurement of vital signs and blood samples collection. After completing 8 weeks on each medication, muscle nerve activity will be measured while performing the same exercises described in the baseline study visit.

Arms:
arm 1: The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 8 weeks. Following the 8 week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. arm 2: The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 8 weeks. Following the 8 week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.

Interventions: intervention 1: Eplerenone intervention 2: Amlodipine intervention 3: Microneurography intervention 4: Rhythmic handgrip exercise intervention 5: Sustained hand grip intervention 6: Forearm blood flow intervention 7: Arm cycling exercise intervention 8: Cold Pressor test
Intervention descriptions: intervention 1: The subject will be started on Eplerenone (Inspra) 50-200mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued intervention 2: The subject will be started on Amlodipine (Norvasc) 2.5 -10mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. intervention 3: Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study. intervention 4: Subjects will perform a rhythmic handgrip exercise at 30% or 45% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise intervention 5: Subjects will perform a sustained handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise. intervention 6: Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip exercise intervention 7: Subjects will perform a cycling arm exercise with a stationary cycling device. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this exercise. intervention 8: Subjects will place hand in cold water with ice for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline, during and 2 minutes after the test.

Protocol document:
Prot_SAP_000.pdf: 
1 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
Protocol 
 
Title: The Role of Aldosterone on Exercise Pressor Reflex in Hypertension , NCT01996449 
December 12, 2018 
Investigators 
 
Principal Investigator: Wanpen Vongpatanasin, M.D., Cardiology Division, Department of 
Medicine, University of Texas Southwestern Medical Center 
 
Participating Institutions: University of Texas Southwestern Medical Center 
 
 
 
 
 
  
Funding: 
 NIH 
 
 
Table of Contents: 
 
Protocol Section 
 
 
 
 
                          Pages 
 
1) Introduction  
 
 
 
 
                              2  
2) Background 
 
 
 
 
                              3 
3) Concise Summary of Project                                                    4 -5 
 
 
  
4) Study Procedures                                                                        6-9 
5) Criteria for Inclusion of Subjects               
                              9 
6) Criteria for Exclusion of Subjects 
 
                              9-10 
7) Sources of Research Material  
                                         10 
8) Recruitment Methods and Consenting Process                          10 
9) Potential Risks  
 
 
 
                              10 
10) Subject Safety and Data Monitoring  
                              10-13 
11) Procedures to Maintain Confidentiality                                       13 
12) Potential Benefits 
                                                               13-14 
13) Biostatistics                                                                                 14-15 
14) References 
 
 
 
 
                               16 


2 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
1. Introduction and Purpose: 
 
Hypertensive patients often show an exaggerated rise in blood pressure (BP) during exercise—
sometimes to the levels that raise safety concern. The mechanisms responsible for exercise 
pressor reflex (EPR) overactivity in hypertension remain unknown but an increasing body of 
evidence suggests a role for aldosterone in regulating resting central sympathetic outflow in both 
hypertensive rats and humans. Furthermore, local aldosterone synthesis in the brain has been 
shown to contribute to sympathetic activation and hypertension in SHR and Dahl-salt sensitive 
rats despite normal circulating levels of aldosterone. Whether aldosterone contributes to 
excessive sympathoexcitation and BP elevation during exercise remains to be investigated. 
Therefore, we now propose parallel translational studies in hypertensive patients with primary 
hypertension and a secondary form of hypertension caused by adrenal overproduction of 
aldosterone (primary aldosteronism) to systematically investigate the contribution of aldosterone 
to the generation of EPR dysfunction.   
 
Major New Hypothesis: Aldosterone augments the EPR by selectively potentiating muscle 
mechanoreflex activity in hypertensive humans. We further hypothesize that this effect of 
aldosterone is mediated by its direct action on the central nervous system and that 
mineralocorticoid receptor (MR) antagonists constitute an effective treatment for EPR 
overactivity in hypertension, independent of reductions in resting BP. 
 
 
In patients with uncomplicated essential hypertension (EH), hypertensive patients with primary 
aldosteronism (PA), and normotensive (NT) controls matched for age, gender, ethnicity, and 
BMI, we will perform multiple exercise interventions to determine if: 
a. Sympathetic nerve activity (SNA) and BP responses to EPR activation during rhythmic 
handgrip exercise and mechanoreflex activation during passive arm cycling are 
augmented in patients with EH and PA. 
b. SNA and BP responses to metaboreflex activation during post handgrip arm occlusion 
are unaltered in the EH and PA groups. 
c. Indices of central command (increases in skin SNA, heart rate, and rating of perceived 
effort) input during exercise are similarly increased in EH and PA groups compared to the 
NT group. In addition, the sensitivity of the arterial baroreflex to modulate SNA and BP 
responses to exercise is unaltered during rhythmic and static handgrip in EH and PA 
groups. 
d. Augmented EPR and mechanoreflex sensitivity in a subset of PA patients with 
aldosterone-producing adenoma (APA) is reversible upon surgical removal of the tumor. 
e. MR antagonists constitute an effective treatment for EPR dysfunction by attenuating 
mechanoreflex overactivity in patients with EH and PA. Such effects have not been 
observed with treatment with amlodipine despite similar reductions in resting BP. 


3 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
2. Background:  
 
Hypertensive patients are known to display exaggerated rise in blood pressure (BP) during exercise but 
the underlying mechanisms are poorly understood. Normally, exercise is accompanied by decreased 
parasympathetic activity and increased sympathetic activity caused by central command and activation 
of thin fiber muscle afferents that reflexively increase sympathetic outflow and BP. Traditionally, muscle 
afferents were dichotomized as metaboreceptors, which are activated slowly and only during intense or 
ischemic muscle contraction, or mechanoreceptors, which respond quickly to even mild deformation of 
their receptive fields. The increase in SNA and BP caused by activation of these receptors, known as 
exercise pressor reflex, is normally buffered by activation arterial baroreceptors, which are reset to 
operate at higher BP range but at the same level of sensitivity. Our recent work in spontaneously 
hypertensive rats (SHR) and patients with essential hypertension indicated an exaggerated rise in 
sympathetic nerve activity (SNA) and BP during muscle contraction even in the absence of congestive 
heart failure. Furthermore, the latency of the sympathetic response during exercise is much shorter than 
normal and the threshold level of exercise intensity required to increase muscle SNA is much lower than 
normal, implicating mechanoreceptor mediation. Mechanisms responsible for overactive exercise 
pressor reflex (EPR) in hypertension remain unknown but an increasing body of evidence suggested a 
role for aldosterone in regulating resting central sympathetic outflow in both hypertensive rats and 
humans. Furthermore, local aldosterone synthesis in the brain has been shown to contribute to 
sympathetic activation and hypertension in the SHRs and Dahl-salt sensitive rats despite normal 
circulating levels of aldosterone. Whether aldosterone contributes to excessive sympathoexcitation and 
BP elevation during exercise remains unknown. Therefore, we now propose parallel translational studies 
in hypertensive patients with primary hypertension and secondary form of hypertension caused by 
adrenal overproduction of aldosterone (primary aldosteronism), using multiple interventions to directly 
activate muscle mechanoreceptors, metaboreceptors, or arterial baroreceptors during exercise and 
microelectrode recordings of SNA to measure the reflex response. The distinctive features of this 
proposal include: (1) the use of state-of- the-art techniques (microelectrode recordings of SNA) to directly 
test mechanistic hypotheses in conscious humans; (2) assessment of mechanoreflex using a new 
paradigm which is developed in our laboratory which evokes sustained elevation in SNA and BP than 
other methods previously described in humans; and (3) the use of complimentary approach to asses 
central vs. peripheral effects of aldosterone on neural control of circulation.  
 
 
Significance and Cardiovascular Relevance: Hypertension is a major cause of cardiovascular 
morbidity and mortality in the United States and many countries worldwide. Excessive elevation in BP 
during exercise has been shown to contribute to impaired exercise tolerance in hypertensive patients 
even in the absence of coronary artery disease or left ventricular dysfunction 1-4. Furthermore, numerous 
epidemiological studies indicated that BP during exercise predicts development of left ventricular 
hypertrophy 5, 6, stroke, myocardial infarction, and death 7-9, independent of resting BP. Accordingly, 
current guidelines prohibit any exercise in hypertensive patients if BP during exercise is 220/105 or above 
for safety reasons 10, 11. Therefore, exercise prescription is often limited in hypertensive patients with an 
enhanced EPR 12. Because most current antihypertensive drugs approved are much less effective in 
reducing BP at rest than during exercise 9, 13-18, a more complete mechanistic understanding of the 
augmented pressor response to exercise in human hypertension could lead to effective antihypertensive 
treatment. This will in turn allow more hypertensive patients to engage in regular exercise and enjoy the 
cardiovascular benefits of exercise, which is also an important nonpharmacologic treatment of 
hypertension. The information derived from our proposed studies will be pertinent not only to patients 
with primary hypertension but also those with primary aldosteronism which has been identified in 5-13% 
of unselected patients with hypertension in the community and primary care practice 19, 20 and up to 20% 
of patients with resistant hypertension referred to the tertiary care hypertension clinic 21. 
 
 
3.Concise Summary of Project: 
 


4 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
General Methods BP will be measured with an oscillometric device (Welch Allyn, N.C.).  
(1) Microneurography. With the subject supine, we will measure blood pressure, heart rate, and muscle 
SNA with microelectrodes in the arm (median nerve or radial nerve or posterior cutaneous nerve) or leg 
(peroneal nerve). The nerve signals are amplified, filtered, rectified and integrated to obtain a mean 
voltage display of SNA. The criteria for an acceptable recording of muscle SNA has been previously 
described 15. Sympathetic bursts will be detected by inspection of the filtered and mean voltage 
neurograms. A deflection on the mean voltage display is counted as a "burst" if it has a minimal signal 
to noise ratio of 2:1. SNA will recorded at rest in all protocols.  
 
(2) Reflex Interventions: (a) Handgrip exercise . Rhythmic HG (RHG) will be performed in the 
nondominant arm at 40 beats per minute (50% cycle duty) at 30% and 45% maximal voluntary contraction 
(MVC), each for 3 minutes. Static HG (SHG) will be performed at 30% MVC for 2 minutes. Ratings of 
perceived exertion (RPE) will be obtained at the end of each exercise by using a 6- to 20-unit Borg scale. 
For safety, the study will be terminated if BP during exercise at any time point is 220/105 mmHg or above 
in accordance with current guidelines 10, 11. (b) Post-Handgrip Exercise Circulatory Arrest (PECA). During 
the last 5 sec of static HG exercise, a pneumatic cuff on the upper exercising arm will be inflated to 50 
mmHg above systolic BP for 2 minutes to activate the metaboreflex. (c) Passive arm cycling. To activate 
mechanoreflex, the subject’s nondominant hand will be strapped to one of the arm pedal of the arm 
ergometer while the investigator put their hand on the other pedal to move the arm ergometer at 80 r.p.m. 
Subjects will be asked to relax their arms during passive arm cycling for 5 minutes. Surface 
electromyography (EMG) on the bicep muscles (Noraxon, Scottsdale, AZ) will be used to monitor the 
muscular activity and a biofeedback device to assist the subjects with relaxation of their arm muscles. (d) 
Arterial baroreflex sensitivity. Arterial baroreflex control of muscle SNA and HR will be assessed during 
bolus injection of nitroprusside (NTP) and phenylephrine (PE) using the modified Oxford technique 22. 
For safety reasons, NTP will not be given if BP is ≤90/60 mmHg and PE will not be given if BP is ≥ 
160/100 mmHg immediately prior to administration. 
 
(3) Cardiopulmonary testing: A subset of subjects who opt for this optional testing, will be asked to cycle 
on a rate-independent ergometer to measure peak VO2 using a metabolic cart (Medgraphics) during a 
separate visit. An established cycle ergometer ramp protocol will be performed. Standard indications for 
termination of exercise testing will be employed. Respiratory gases inclusive of VE, VO2, VCO2, and RER 
will be measured continuously throughout the exercise test. We will also measure continuous ECG and 
maximal heart rate, maximal oxygen uptake (peak VO2), pulmonary ventilation (VE), ventilatory 
equivalents for oxygen (VE/VO2), carbon dioxide (VE/CO2), end-tidal partial pressure of oxygen (PETO2), 
and carbon dioxide (PETCO2). Simultaneous cardiac output (CO) measurement will be performed at rest 
and during steady state exercise testing by inert gas rebreathing method using Inncor system (Innovision 
A/S, Odense, Denmark). Cardiac output will be measured separately from maximal exercise testing in 
three conditions: (1) at rest, (2) at 20 Watts, and (3) at 50% peak VO2/work load. After the participant 
has completed the peak exercise testing protocol and rested 5 minutes, exercise stress 
echocardiography will be performed at 50% of maximal workload. 
 
 
Premenopausal women will be studied during the early follicular phase (2-4 days after the onset of 
menstruation) to minimize confounding influence of sex hormones on SNA 23. Women taking oral 
contraceptives will be studied during low hormone (LH) phase (i.e., placebo pills). 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent/Device 
A. Amlodipine  
Trade name: Norvasc 
Chemical Formula: 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-l,4-dihydro-6-
methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate 


5 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
Source: Pfizer Inc. 
            Pharmacology: Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of 
vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary 
vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with 
vasospastic angina. 
Toxicity: Peripheral edema, fatigue, dizziness, hypotension, and gingival hyperplasia. 
 
B. Eplerenone  
Trade name: Inspra 
Chemical Formula: Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3oxo-, γ-lactone, methyl 
ester, (7α,11α,17α) 
Source: Pfizer Inc. 
            Pharmacology: Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, 
a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs 
primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS 
mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to 
mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, 
and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly 
other mechanisms. 
Toxicity: hyperkalemia, orthostatic hypotension, and acute renal failure 
 
 
 
4.Study Procedures: 
 
Experiments will be performed on 3 groups of nondiabetic subjects 1) stage I (140-159/90-99 mmHg) 
subjects with EH, 2) stage I hypertensive subjects with PA, and 3) NT controls. The diagnosis of PA will 
be established based on the current Endocrine Society guidelines 24. As part as standard medical 
care, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, central 
sympatholytic drugs and diuretics will be discontinued for at least 2 weeks and MR antagonists will be 
discontinued for at least 6 weeks to avoid interference with biochemical testing 24. During the period of 
biochemical evaluation, subjects will be treated with calcium channel blockers, hydralazine, and/or 
alpha-adrenergic receptor blockers, which do not interfere with measurement of plasma renin activity 
(PRA) or aldosterone 24. The screening evaluation is considered to be positive if plasma aldosterone 
levels are > 15 ng/dL and PRA are < 1 ng/ml/hr. Diagnosis of PA is established by presence of 
nonsuppressible aldosterone production after a salt loading test according to the guidelines 24. Subjects 
with biochemical confirmation of PA will undergo adrenal vein sampling (AVS) as part of standard 
care to distinguish between unilateral vs. bilateral adrenal overproduction of aldosterone. We need to 
determine if association between aldosterone and SNA as well as BP is independent of dietary pattern, 
including caloric intake. Dietary pattern will be assessed by food recall using the Automated Self-
Administered 24-Hour (ASA24®) Dietary Assessment Tool (https://epi.grants.cancer.gov/asa24/).   
 
 
The following procedures are experimental: 
 
We plan to assess muscle SNA and MAP at rest, during passive one-arm cycling exercise (see aim 2a), 
RHG, and SHG followed by PECA in 15 EH and 15 PA subjects (not included in previous aims). Subjects 
will be randomized to receive eplerenone (50-200 mg/day) or amlodipine (2.5-10 mg/day) each for 8 
weeks, using randomized, double-blinded, crossover design. The rationale for using amlodipine is that 
previous studies have shown that this drug reduces BP without affecting resting SNA 26. BP and serum 
K will be monitored every 2 weeks. Each subject will be started with 50 mg eplerenone/day or 2.5 mg 
amlodipine/day. If BP remains above 140/90 mmHg at week 2, the dose of eplerenone will be increased 
to 100 mg/day, whereas amlodipine will be increased to 5 mg/day. If BP remains elevated at week 6, 


6 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
eplerenone will be increased to 200 mg/day and amlodipine to 10 mg daily. This dose titration of 
amlodipine and eplerenone is chosen because it was shown to cause equivalent reductions in BP in 
hypertensive patients in a large clinical trial 27. If hyperkalemia develops with eplerenone, the dose will 
be reduced by 50% and serum K will be rechecked in 2 weeks (see detail in section 10d). We predict that 
eplerenone will attenuate the increase in SNA and MAP during HG and passive arm cycling in subjects 
with EH and PA without affecting SNA and BP responses to PECA. Amlodipine will have no effect on 
SNA or BP in the same subjects during all exercise interventions, despite causing similar reduction in 
resting BP.  
 
Visit#1 (week 0): Obtain blood samples for basic metabolic panel, resting levels of plasma direct renin, 
aldosterone (aldo), norepinephrine (NE), and fasting plasma glucose and insulin. Then, assess muscle 
SNA and MAP at rest, during passive one-arm cycling exercise for 5 minutes (see general method 
#2c). During passive arm cycling, surface electromyography (EMG) on the bicep muscles (Noraxon, 
Scottsdale, AZ) will be used to monitor the muscular activity and a biofeedback device to assist the 
subjects with relaxation of their arm muscles.  Then, subjects will be asked to perform, RHG at 30% 
and 45% MVC each for 3 minutes, and SHG at 30% MVC followed by PECA for 2 minutes. Each 
exercise intervention will be separated by at least 30 minutes. After completion of exercise, each 
subject will be randomized to receive Eplerenone at the dose of 50 mg once daily or Amlodipine 2.5 mg 
once daily. 
 
Visit#2 (2 weeks later): Subjects will return for BP check and blood draw for basic metabolic panel. If 
BP is < 90/60 mmHg, subjects will be excluded from the study. If subjects BP > 140/90, the dose of 
Amlodipine will be increased to 5 mg once daily or Eplerenone will be increased to 100 mg once daily. 
3cc of blood will be drawn for basic metabolic profile. If If hyperkalemia develops with eplerenone, the 
dose will be reduced by 50% and serum K will be rechecked in 2 weeks. 
 
Visit#3 (2 weeks later): Subjects will return for BP check and blood draw. If BP is < 90/60 mmHg, the 
dose of study drugs will be reduced by 50%. If subjects BP > 140/90, the dose of Amlodipine will be 
increased to 7.5 mg once daily or Eplerenone will be increased to 150 mg once daily. 3cc of blood will 
be drawn for basic metabolic profile. If hyperkalemia develops with eplerenone, the dose will be 
reduced by 50% and serum K will be rechecked in 2 weeks.  
 
Visit#4 (2 weeks later): Subjects will return for BP check and blood draw. If BP is < 90/60 mmHg, the 
dose of study drugs will be reduced by 50%. If subjects BP > 140/90, the dose of Amlodipine will be 
increased to 10 mg once daily or Eplerenone will be increased to 200 mg once daily. 3cc of blood will 
be drawn for basic metabolic profile. If hyperkalemia develops with eplerenone, the dose will be 
reduced by 50% and serum K will be rechecked in 2 weeks. 
 
Visit#5 (2 weeks later): Subjects will return for blood draw for basic metabolic panel, resting levels of 
plasma direct renin, aldosterone (aldo), norepinephrine (NE), and fasting plasma glucose and insulin. 
Then, assess muscle SNA and MAP at rest, during passive one-arm cycling exercise for 5 minutes (see 
general method #2c). During passive arm cycling, surface electromyography (EMG) on the bicep 
muscles (Noraxon, Scottsdale, AZ) will be used to monitor the muscular activity and a biofeedback 
device to assist the subjects with relaxation of their arm muscles.  Then, subjects will be asked to 
perform RHG at 30% and 45% MVC each for 3 minutes, and SHG at 30% MVC followed by PECA for 2 
minutes. Then, subjects will be given BP medications in the remaining arm (either Amlodipine 2.5 mg 
once daily or Eplerenone at the dose of 50 mg once daily). 
 
Visit#6 (2 weeks later): Subjects will return for BP check and blood draw. If BP is < 90/60 mmHg, 
subjects will be excluded from the study. If subjects BP > 140/90, the dose of Amlodipine will be 
increased to 5 mg once daily or Eplerenone will be increased to 100 mg once daily. 3cc of blood will be 
drawn for basic metabolic profile. If hyperkalemia develops with eplerenone, the dose will be reduced 
by 50% and serum K will be rechecked in 2 weeks. 
 


7 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
Visit#7 (2 weeks later): Subjects will return for BP check and blood draw. If BP is < 90/60 mmHg, the 
dose of study drugs will be reduced by 50%. If subjects BP > 140/90, the dose of Amlodipine will be 
increased to 7.5 mg once daily or Eplerenone will be increased to 150 mg once daily. 3cc of blood will 
be drawn for basic metabolic profile. If hyperkalemia develops with eplerenone, the dose will be 
reduced by 50% and serum K will be rechecked in 2 weeks. 
 
Visit#8 (2 weeks later): Subjects will return for BP check and blood draw. If BP is < 90/60 mmHg, the 
dose of study drugs will be reduced by 50%. If subjects BP > 140/90, the dose of Amlodipine will be 
increased to 10 mg once daily or Eplerenone will be increased to 200 mg once daily. 3cc of blood will 
be drawn for basic metabolic profile. If hyperkalemia develops with eplerenone, the dose will be 
reduced by 50% and serum K will be rechecked in 2 weeks. 
 
Visit#9 (8 weeks later): Subjects will return for blood draw for basic metabolic panel, resting levels of 
plasma direct renin, aldosterone (aldo), norepinephrine (NE), and fasting plasma glucose and insulin. 
Then, assess muscle SNA and MAP at rest, during passive one-arm cycling exercise for 5 minutes (see 
general method #2c). During passive arm cycling, surface electromyography (EMG) on the bicep muscles 
(Noraxon, Scottsdale, AZ) will be used to monitor the muscular activity and a biofeedback device to assist 
the subjects with relaxation of their arm muscles.  Then, subjects will be asked to perform RHG at 30% 
and 45% MVC each for 3 minutes, and SHG at 30% MVC followed by PECA for 2 minutes. End of study. 
 
5. Inclusion Criteria 
Experiments will be performed on 3 groups of nondiabetic human subjects 1) stage I (140-159/90-99 
mmHg) subjects with essential hypertension, 2) stage I hypertensive subjects with primary aldosteronism, 
and 3) normotensive controls. Only subjects without CHF, any heart diseases, or target organ disease 
with eGFR ≥ 90 ml/min/1.73 m2, can participate in the study.  
 
 
6. Exclusion Criteria 
 
 
 
 (1) Any evidence of cardiopulmonary disease, left ventricular hypertrophy or systolic dysfunction 
by echocardiography.  
 
 
(2) Blood pressure averaging ≥160/100 mmHg 
 
 
(3) Estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2 
 
 
(4) Diabetes mellitus or other systemic illness   
 
 
 
   
 
(5) Pregnancy 
  
(6) Hypersensitivity to nitroprusside, phenylephrine, amlodipine or eplerenone 
 
 
(7) Any history of substance abuse or current cigarette use  
 
 
(8) Any history of psychiatric illness  
 
(9) History of malignancy 
 
 
 
7. Sources of Materials: 
 
  
 
The physician-investigators will have access to the patients' medical records. We also will have 
access to the Dallas Heart Study database, as all participants gave their written consent to be 
contracted for future research studies. The Dallas Heart Study health survey questionnaire data 
will be used to identify potentially eligible subjects to be recruited for our studies. However, all the 
new hemodynamic and hormonal data at rest and during handgrip exercise (SNA, BP, HR, plasma 
NE, insulin, glucose, serum K, renin, serum aldosterone, baroreflex sensitivity) will be obtained 
solely for research purposes.      
 
 
8. Recruitment Methods and Consenting Process: Informed written consent will be obtained from all 
subjects using consent forms approved by the UT Southwestern IRB. The physician-investigators will 
interview all potential subjects and will explain the nature of all experimental procedures in detail. They 


8 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
also will perform a pertinent medical history and physical examination. Normal controls and subjects with 
essential hypertension will be recruited via advertisement in the campus and letter of invitation (only for 
DHS subjects who had given consent for contact for participation in future studies). PA subjects will be 
recruited from the hypertension clinic at Aston ambulatory center by the P.I. and study investigators.  
.  
 
9. Potential Risks: 
The potential risks are related to: a) microneurography, b) intravenous infusion of nitroprusside 
(NTP), c) intravenous infusion of phenylephrine (PE), d) administration of eplerenone, e) 
venipuncture, and f) administration of amlodipine, and g) Potential risk of handgrip exercise. 
 
a) The potential risks of microneurography: 10% of subjects may experience transient arm or 
legtiredness, or increase sensitivity to touch (hyperesthesia), motor weakness  lasting less than 
1 week. Since 1979, microneurography has been performed on more than several thousand 
subjects without permanent complications related to procedure.  
 
 
b) The potential risks of administration of nitroprusside is flushing, hypotension and tachycardia. 
For safety reasons, NTP will not be given if resting BP is ≤90/60 mmHg. 
 
c) The potential risk of administration of phenylephrine is excessive increase in BP. PE will not be 
given if resting BP is ≥ 160/100 mmHg. 
 
d) Potential risk of Eplerenone is hypotension, hyperkalemia, and renal dysfunction. 
 
e) Potential risks of venipuncture are infection, bleeding, and vasovagal reaction.  
 
f) Potential risk of amlodipine is hypotension, gingival hyperplasia, and lower extremity edema. 
 
g) Potential risk of handgrip exercise is hand discomfort and excessive increase in BP. However, 
study will be terminated if BP during exercise at any time point is 220/105 mmHg or above for 
safety reasons according to the current guidelines 10, 11. 
 
h) Potential Risks for exercise testing: There is a finite probability of an adverse cardiovascular 
event (myocardial infarction or sustained ventricular tachycardia: 1.2/10,000) and death 
(<~1/10,000) in individuals undergoing exercise testing.  Exercise testing will be terminated based 
on standard indications, including ST-segment elevation, decreased systolic blood pressure > 10 
mmHg with exercise, sustained ventricular tachycardia. Resuscitative equipment and study 
personnel certified in Advanced Cardiovascular Life Support (ACLS) will be nearby in the rare 
case of a medical emergency. If there is cardiovascular or respiratory compromise, the “Code 
Blue” system will be triggered in the UT Southwestern campus while ACLS is administered by 
trained personnel within the room. A defibrillator is located in the exercise lab and can be 
immediately available should the situation arise. An attending cardiologist will be immediately 
available by phone call as needed. 
 
 
 
10. Subject Safety and Data Monitoring:  
 
a) Microneurography will be performed under the supervision of Dr. Vongpatanasin who has 
extensive experience.  A stimulus isolation unit (special electronic circuit) will be used to prevent 
electrocution from the recording apparatus. Subjects will be given a microneurographic 
questionnaire to report any adverse reactions occurring up to one week after the study.  
 


9 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
b) All subjects will have a routine history and physical examination performed by the physician-
investigators. In addition, hospital medical records will be reviewed prior to the initiation of these 
studies. Venipuncture will be performed by research nurse at the CTRC, using sterile technique. 
 
c) ACLS-certified personnel, including a board certified cardiologist, will be present during all 
experiments. Resuscitative equipment and drugs will be available in the laboratory. Blood 
pressure and the subject’s heart rate will be monitored continuously during all experiments.  
During baroreflex testing, NTP will not be given if resting BP is ≤90/60 mmHg and PE will not be 
given if BP is ≥ 160/100 mmHg.  
 
During handgrip exercise intervention, study will be terminated if BP at any time point is 220/105 
mmHg or above for safety reasons according to the current guidelines 10, 11.  
 
d) During treatment with eplerenone in aim 1e, BP and serum K will be monitored every 2 weeks. 
Each subject will be started with 50 mg eplerenone daily or 2.5 mg amlodipine daily. If BP remains 
above 140/90 mmHg at week 2, the dose of eplerenone will be increased to 100 mg daily, whereas 
amlodipine will be increased to 5 mg daily. If BP remained elevated at week 6, eplerenone will be 
increased to 200 mg daily and amlodipine to 10 mg daily If subjects develop hypotension (BP < 
90/60 mmHg persistently), the eplerenone and amlodipine will be reduced by 50%. BP will be 
rechecked within 2 weeks in these subjects. 
 
This dose range and pattern of titration of eplerenone and amlodipine is chosen because it was 
shown to produce equivalent reduction in BP in a large clinical trial 27 and there were no serious 
adverse events related to either drug with this dose range 27, 28. The incidence of hyperkalemia (K 
> 5.5 mmol/L) was between 1.1-3.0% in the eplerenone group 27, 28 and 1.5% in the amlodipine 
group 27 
 
If subjects develop serum K between 5.5-6.0 mmol/L with eplerenone, the dose will be reduced 
by half and serum K will be rechecked in 2 weeks.  
 
Those who develop hypokalemia during the follow up visit (K 3.0-3.5 mmol/L) will be started on K 
supplement 40 mmol daily and serum K will be rechecked in 2 weeks. 
 
Subjects who develop severe hypokalemia (< 3.0 mmol/L) or hyperkalemia ( > 6.0 mmol/L), EKG 
will be obtained immediately and the study procedures will be discontinued in these subjects. 
Subjects will be transferred to the emergency department for further evaluation and management. 
Known adverse events and the likelihood of occurrence are described in the IRB-approved informed 
consent document. 
The classification of adverse events will follow the Common Toxicity Criteria used by the National Cancer 
Institute at http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf.  Attribution of an adverse event to study 
procedures will be in accordance with IRB terminology ("definite," "probable," "possible," "unknown," or 
"unrelated" relationship). 
Ms. Beverley Adams-Huet, our collaborating investigator, will perform the aggregate analysis of adverse 
event reports. 
In the absence of adverse events, data analysis will occur at weekly intervals and reviewed at weekly lab 
meetings. 
Monitoring will be performed in conjunction with each subject's experience with study procedures, and 
conclusions of the monitoring reported to the IRB and CTRC no less than every 12 months in accordance 


10 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
with IRB and CTRC requirements. Such progress reports will include a discussion of data quality and 
timeliness, participant recruitment, accrual and retention; participant risk versus benefit, and other factors 
than can affect study outcome. 
Monitoring reported to the IRB and CTRC will also include consideration of factors external to the study 
when interpreting the data, such as scientific or therapeutic developments that may have an impact on 
the safety of the participants or the ethics of the study. 
Stop Points:  Any of the following criteria will constitute stop points.   
• 
Refractory hyperkalemia defined as more than one episode of serum potassium level > 5.5 
mEq/L.  The second episode must be confirmed by repeat measurement in the core laboratory. 
• 
Withholding of study medication for > 4 weeks for whatever reason. 
• 
Any reason including serious adverse events that results in participant’s inability to continue with 
study protocol and procedures.  
• 
Severe hypertension defined as persistent elevation of systolic BP > 180 mmHg or diastolic BP > 
110 mmHg on 3 consecutive measurements after randomization 
• 
Refractory hypotension defined as persistent systolic BP < 100 mmHg   
• 
Pregnancy 
• 
Development of diabetes mellitus or a new medical condition necessitating administration of ACE 
inhibitor, angiotensin receptor blocker, or spironolactone 
Conditions for temporarily halting study medications: These include 1) sudden increase in serum 
creatinine of > 50% of the baseline value obtained on the CTRC visit prior to randomization; 2) Severe 
uncontrolled hypertension in the outpatient setting defined as elevation of systolic BP > 180 mmHg or 
diastolic BP > 110 mmHg on two consecutive occasions measured at least 48 hours apart despite effort 
to lower BP by diet or nonpharmacologic intervention. 
 
  
Conditions for permanently halting study medication in an individual:  A stop point will be 
defined as any serious adverse event that in the opinion of the Principal investigator could be reasonably 
attributed to the study intervention. At this time the participants study medication will be permanently 
discontinued and a close out visit will be scheduled.   
  
 
 
Conditions for stopping the protocol entirely: Conditions for stopping the entire protocol are 1) 
development of severe hyperkalemia (serum K > 6.0 mEq/L) or acute renal insufficiency (eGFR reduces 
by > 30%) in 1 subject or more after they have been randomized to study drug, (2) any evidence of 
myocardial ischemia or infarction (chest pain, EKG changes), (2) any new onset of sustained cardiac 
arrhythmia including atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, or ventricular 
fibrillation; (3) any death. Under such circumstances, the study will not resume without IRB and CTRC 
approval.   
Reports to Federal, University, and hospital offices 
The PI will immediately report all unexpected and any serious adverse events and the recommendations 
derived from data and safety monitoring (such as continuation or conclusion of the trial) to the IRB, CTRC, 
hospital, FDA, and NIH.   
The PI will immediately notify NIH of actions, if any, taken by the IRB as a result of its continuing review.  
The PI will submit copies of FDA reports about adverse events to the CTRC as well as IRB. 


11 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
The PI will anonymize all reports of local adverse events submitted to the IRB and CTRC to protect a 
subject’s privacy. 
The PI will educate all key personnel about the requirements to report unexpected and serious adverse 
events to the IRB, CTRC, and other agencies and offices. 
 
 
11. Procedures to Maintain Confidentiality   
 
 
1.  Information will be given only to the physician-investigators.   
2.  The nature of the information concerns pertinent medical and social history. 
3. The purpose of the disclosure is solely for research purposes, in particular to determine whether 
potential subjects meet criteria for inclusion or exclusion and to identify specific subgroups of 
subjects.     
4.  The subject’s right of confidentiality will be given strict priority. No mention of the subjects’ 
identities will be made either directly or indirectly in oral or written presentation of this work. The 
investigators, who are physicians, will be responsible for providing medical care in the event of 
any adverse effects to the subjects.  
5.  Copies of executed consent forms and all experimental records will be in the locked cabinet in 
our cardiovascular physiology laboratory in H4.136. All medical and biographical information will 
be held strictly confidential and no disclosures of personal identity will be allowed unless 
specifically requested by the subject. Copies of executed consent forms, as well as the 
experimental log book, are kept in a locked file cabinet in this laboratory. 
 
6.  Data management: The data repository will be developed using the Microsoft SQL Server 
 
relational database management system with Microsoft Access as the user interface.  
 
Data will be centralized and maintained upon a secure centralized network server and is backed 
up on a rotating schedule.  This system allows access to the database throughout UTSW campus 
university network but database privileges are only allowed on an as-needed basis and must be 
approved by the Principal Investigator.  Data that is electronically captured will be reviewed before 
being merged into the database.  Audit logs of all data access will be maintained for security 
purposes.  De-identified data will be shared with collaborating investigators according to 
University rules and regulations. 
 
12. 
Potential Benefits of the proposed Research to the Subjects and Others 
Hypertensive patients are known to have exaggerated rise in BP during exercise, which poses 
substantial health risks independent of resting BP 5-9. However, the underlying mechanisms of 
augmented exercise-induced BP elevation in human hypertension remain unknown. Our current 
research proposal is designed to assess the role of sympathetic nervous system and sympathetic 
mediated vasoconstriction during exercise in hypertensive patients, which may lead to 
identification of new drug target or treatment for augmented exercise pressor response.  
 
1.  Although these experiments are not designed to benefit the subjects directly, all subjects will 
receive monetary reimbursement for participation in the study.  
 
2.  However, the results of these studies may lead to understanding of mechanism of augmented 
exercise-induced BP elevation. If we can confirm that circulating aldosterone or local aldosterone 
synthesis in the central nervous system is the major cause of this abnormality by sensitization of 
mechanoreflex, our work could lead to identification of new action of MR antagonists which can 
prevent excessive rise in BP during exercise in hypertensive patients. This in turn will allow more 
hypertensive patients to participate in regular exercise.   
 


12 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
The anticipated large amount of new knowledge about the role of sympathetic nervous system and 
modulation of sympathetic vasoconstriction in pathogenesis of augmented exercise pressor response 
should justify the performance of this research. We anticipate that the results of our human integrative 
cardiovascular research will provide a new conceptual framework for implicating mechanoreceptor 
sensitization causing reflex sympathetic activation and exaggerated exercise BP response in human 
hypertension. Our study may also lead to identification of the origin of accentuated mechanoreflex and 
exercise intolerance in heart failure.  
 
 
13. Statistical Considerations SAS (SAS Institute, Cary, NC) software will be used for all analyses and 
PROC MIXED for repeated measures 29. Statistical Considerations Sample size and power estimates 
were computed using PASS 11 (NCSS, LLC, Kaysville, UT).  
 
The primary endpoint is muscle SNA (bursts/min, aim 2a, b, d, and e) and skin SNA (%total activity, aim 
2c). Secondary endpoints include SNA % total activity (only for muscle SNA since skin SNA units are 
already in % total activity), MAP, and HR. In all aims, the association between SNA responses and NE, 
insulin resistance variables will be analyzed with Pearson or Spearman correlation coefficients. 
 
To control for resting levels for SNA, BP, or other endpoints which could be affected by drug 
treatment (aim 2e) or surgical removal of tumor (aim2d), the resting or time 0 measurement prior to each 
activity (see fig 12-13) will be analyzed as a control covariate (analysis of covariance approach) in 
repeated measures models. This approach will also increase the precision of the response estimates.  
We will also evaluate changes and % changes from baseline levels to facilitate interpretation of the 
results. Repeated measures (RM) analysis will be conducted with mixed linear models with subject as a 
random effect.  All available data will be included in the analyses, including subjects with missing data. 
Model parameter estimates in the presence of missing data will be made with restricted maximum 
likelihood. Most analyses will include a repeated factor for comparing the activity gradations; covariance 
structure is selected on the basis of information criteria as well as model parsimony. For multiple 
comparisons, adjustments will be made as appropriate with SAS’s simulation adjustment method with a 
family-wise error rate of 0.05 and fixed seed 29. 
 
Due to our prior success with frequency matching enrollment 25, 30-32, study groups should be 
balanced with respect to gender, menopausal status, ethnicity, age, and BMI and we do not anticipate 
needing additional covariate adjustments. However, we will assess effects of these and other potential 
confounding variables from e.g., 24h urine Na, descriptive statistics, scatter plots, box plots, and by 
modeling the covariate.  
 
 
A two-period crossover study of amlodipine vs eplerenone medication will be conducted in 15 PA and 15 
EH subjects. This sample size accounts for ~20% attrition and is powered for a separate crossover 
analysis for each group to detect a mean difference of 6 bursts/min (std=8, =.7) when comparing the 
primary endpoint of SNA between the two medication phases. With 12 subjects completing both 
medication crossover phases, this study has power of 0.88 at alpha=0.05. Between group response 
differences are not a primary hypothesis; hence are not evaluated for power.  Randomization: Stratified 
by EH and PA, the order of amlodipine and eplerenone treatment will be determined by blocked 
randomization. Statistical analysis:  For each study group, descriptive statistics and 95% CI will be used 
to summarize responses of the two medication phases of this crossover study.  A mixed linear model 
with repeated factors to assess the activity level and medication effect plus their interaction will be 
constructed. Treatment sequence effect will be evaluated in the models. To account for reduction in BP 
after each drug treatment, resting BP will be analyzed as baseline covariates. Other analyses include 
controlling for final medication dose as potential confounding factor and evaluating differences between 
the PA and EH groups with regard medication response using models that include PA and EH groups to 
directly and efficiently assess the group by MR antagonist interaction component. 


13 STU072012-066, Vongpatanasin, Form A3, Mod_7, 12-12-18 
 
         
14. REFERENCES 
1. 
Fagard R, Staessen J, Amery A. Maximal aerobic power in essential hypertension. Journal of 
hypertension 1988;6:859-65. 
2. 
Marraccini P, Palombo C, Giaconi S, Michelassi C, Genovesi-Ebert A, Marabotti C, Fommei E, 
Ghione S, L'Abbate A. Reduced cardiovascular efficiency and increased reactivity during exercise in 
borderline and established hypertension. Am J Hypertens 1989;2:913-6. 
3. 
Olsen MH, Wachtell K, Hermann KL, Bella JN, Andersen UB, Dige-Petersen H, Rokkedal J, Ibsen 
H. Maximal exercise capacity is related to cardiovascular structure in patients with longstanding 
hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension. Am J 
Hypertens 2001;14:1205-10. 
4. 
Lim PO, MacFadyen RJ, Clarkson PB, MacDonald TM. Impaired exercise tolerance in 
hypertensive patients. Ann Intern Med 1996;124:41-55. 
5. 
Lim PO, Donnan PT, MacDonald TM. Blood pressure determinants of left ventricular wall 
thickness and mass index in hypertension: comparing office, ambulatory and exercise blood pressures. 
J Hum Hypertens 2001;15:627-33. 
6. 
Sung J, Ouyang P, Silber HA, Bacher AC, Turner KL, DeRegis JR, Hees PS, Shapiro EP, Stewart 
KJ. Exercise blood pressure response is related to left ventricular mass. J Hum Hypertens 2003;17:333-
8. 
7. 
Kjeldsen SE, Mundal R, Sandvik L, Erikssen G, Thaulow E, Erikssen J. Supine and exercise 
systolic blood pressure predict cardiovascular death in middle-aged men. Journal of hypertension 
2001;19:1343-8. 
8. 
Lewis GD, Gona P, Larson MG, Plehn JF, Benjamin EJ, O'Donnell CJ, Levy D, Vasan RS, Wang 
TJ. Exercise blood pressure and the risk of incident cardiovascular disease (from the Framingham Heart 
Study). Am J Cardiol 2008;101:1614-20. 
9. 
Filipovsky J, Ducimetiere P, Safar ME. Prognostic significance of exercise blood pressure and 
heart rate in middle-aged men. Hypertension 1992;20:333-9. 
10. 
Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA. American College of 
Sports Medicine position stand. Exercise and hypertension. Med Sci Sports Exerc 2004;36:533-53. 
11. 
Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, Mark DB, 
McCallister BD, Mooss AN, O'Reilly MG, Winters WL, Jr., Antman EM, Alpert JS, Faxon DP, Fuster V, 
Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC, Jr. ACC/AHA 2002 guideline update for 
exercise testing: summary article: a report of the American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing 
Guidelines). Circulation 2002;106:1883-92. 
12. 
Smith SA. Editorial Focus: Exercise in hypertension: Do skeletal muscle reflexes make this a 
dangerous proposition? Am J Physiol Heart Circ Physiol 2010. 
13. 
Taylor SH, Silke B, Ahuja RC, Okoli R. Influence of nicardipine on the blood pressure at rest and 
on the pressor responses to cold, isometric exertion, and dynamic exercise in hypertensive patients. J 
Cardiovasc Pharmacol 1982;4:803-7. 
14. 
Mancia G, Parati G, Grassi G, Pomidossi G, Giannattasio C, Casadei R, Groppelli A, Saino A, 
Gregorini L, Perondi R, et al. Calcium antagonists and neural control of circulation in essential 
hypertension. J Hypertens Suppl 1987;5:S49-55. 
15. 
Duprez D, De Backer T, De Pue N, Hermans L, De Buyzere M, Clement DL. Effects of isradipine 
on peripheral hemodynamic reflex responses in mild-to-moderate essential hypertension. Am J 
Hypertens 1991;4:194S-6S. 
16. 
Dvorak I, Blaha M, Nemcova H. Antihypertensive effect of isradipine on blood pressure at rest 
and during exercise. Am J Hypertens 1991;4:144S-6S. 
17. 
Cardillo C, Musumeci V, Mores N, Folli G. Effects of sustained-release verapamil on 24-hour 
ambulatory blood pressure and on pressor response to isometric exertion in hypertensive patients. J 
Cardiovasc Pharmacol 1989;13 Suppl 4:S31-3. 
18. 
Cleroux J, Beaulieu M, Kouame N, Lacourciere Y. Comparative effects of quinapril, atenolol, and 
verapamil on blood pressure and forearm hemodynamics during handgrip exercise. Am J Hypertens 
1994;7:566-70. 


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19. 
Schwartz G, L., Turner ST. Screening for Primary Aldosteronism in Essential Hypertension: 
Diagnostic Accuracy of the Ratio of Plasma Aldosterone Concentration to Plasma Renin Activity. Clin 
Chem 2005;51:386-94. 
20. 
Rossi GP. Prevalence and diagnosis of primary aldosteronism. Curr Hypertens Rep 2010;12:342-
8. 
21. 
Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism Among 
Black and White Subjects With Resistant Hypertension. Hypertension 2002;40:892-6. 
22. 
Halliwill JR. Segregated signal averaging of sympathetic baroreflex responses in humans. J Appl 
Physiol 2000;88:767-73. 
23. 
Minson CT, Halliwill JR, Young TM, Joyner MJ. Influence of the menstrual cycle on sympathetic 
activity, baroreflex sensitivity, and vascular transduction in young women. Circulation 2000;101:862-8. 
24. 
Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF, 
Jr., Montori VM. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an 
endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:3266-81. 
25. 
Kontak AC, Wang Z, Arbique D, Adams-Huet B, Auchus RJ, Nesbitt SD, Victor RG, 
Vongpatanasin W. Reversible Sympathetic Overactivity in Hypertensive Patients with Primary 
Aldosteronism. J Clin Endocrinol Metab 2010;95:4756–61. 
26. 
Grassi G, Spaziani D, Seravalle G, Bertinieri G, Dell'Oro R, Cuspidi C, Mancia G. Effects of 
amlodipine on sympathetic nerve traffic and baroreflex control of circulation in heart failure. Hypertension 
1999;33:671-5. 
27. 
White WB, Duprez D, St Hillaire R, Krause S, Roniker B, Kuse-Hamilton J, Weber MA. Effects of 
the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic 
hypertension. Hypertension 2003;41:1021-6. 
28. 
Flack JM, Oparil S, Pratt JH, Roniker B, Garthwaite S, Kleiman JH, Yang Y, Krause SL, Workman 
D, Saunders E. Efficacy and tolerability of eplerenone and losartan in hypertensive black and white 
patients. J Am Coll Cardiol 2003;41:1148-55. 
29. 
Littell RC, Milliken GA, Stroup WW, Wolfinger RD, Schabenberger O. SAS for Mixed Models. 2nd 
ed. Cary: SAS Institute; 2006. 
30. 
Menon DV, Wang Z, Fadel PJ, Arbique D, Leonard D, Li JL, Victor RG, Vongpatanasin W. Central 
sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and 
vasoconstriction in humans. J Am Coll Cardiol 2007;50:626-33. 
31. 
Vongpatanasin W, Wang Z, Arbique D, Arbique G, Adams-Huet B, Mitchell JH, Victor RG, 
Thomas GD. Functional sympatholysis is impaired in hypertensive humans. J Physiol 2011;589:1209-
20. 
32. 
Abbas A, Szczepaniak LS, Tuncel M, McGavock JM, Huet B, Fadel PJ, Wang Z, Arbique D, Victor 
R, Vongpatanasin W. Adiposity-independent sympathetic activity in black men. J Appl Physiol 
2010;108:1613-8. 
33. 
Brown H, Prescott R. Applied Mixed Models in Medicine. 2nd ed. West Sussex, England: John 
Wiley & Sons Ltd.; 2006. 
34. 
Vongpatanasin W, Mansour Y, Chavoshan B, Arbique D, Victor GR. Cocaine stimulates the 
human cardiovascular system via a central mechanism of action. Circulation 1999;100:497-502. 
 
 

ICF_001.pdf: 
STU072012-066, Vongpatanasin, Form E - E, Mod_10, 06-07-19 
 
Page 1 of 13 
 
 
 
 
 
DO NOT DISCLOSE 
The University of Texas Southwestern Medical Center at Dallas 
Parkland Health & Hospital System 
Children’s Medical Center 
Texas Scottish Rite Hospital for Children 
Texas Health Presbyterian Hospital of Dallas 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
 
Title of Research: 
The Role of Aldosterone on Exercise Pressor Reflex in 
Hypertension 
 
Experiment E: Effects of MR antagonists on EPR in EH 
and PA. 
 
Funding Agency/Sponsor: 
National Institute of Health 
 
Study Doctors: 
Wanpen Vongpatanasin, MD, Jarett Barry, MD;  
                                                 Hamza Lodhi, MD; Mu Huang, PhD. 
 
 
 
Research Personnel: 
Martha Cruz, Ursa Bezan Petric.  
 
You may call these study doctors or research personnel during regular office hours at 
214-648-3188.  At other times, you may call them at 214-645-8424. 
 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, please ask 
him/her to explain any words or information that you do not clearly understand.  The 
purpose of the study, risks, inconveniences, discomforts, and other important information 
about the study are listed below.  If you decide to participate, you will be given a copy of 
this form to keep. 
 
Why is this study being done? 
The study is being done to find out if signals from the muscles cause the nerve activity 
and blood pressure to increase too much during exercise in patients with high blood 
pressure and high aldosterone hormone (a hormone release from adrenal gland above 
your kidneys that can increase blood pressure). 
 
Why is this considered research?  
 This is a research study because we want to find out if signals from the muscle cause 
nerve activity and blood pressure to increase too much during exercise in patients with 
high blood pressure and high levels of a hormone aldosterone. 
 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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Page 2 of 13 
 
 
 
 
 
DO NOT DISCLOSE 
The following definitions may help you understand this study:  
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research. 
 Researchers means the study doctor and research personnel at the University of 
Texas Southwestern Medical Center at Dallas and its affiliated hospitals. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have high blood pressure 
from high aldosterone hormone or have high blood pressure with normal aldosterone 
hormone. 
 
Do I have to take part in this research study?” 
No.  You have the right to choose whether you want to take part in this research study.  
If you decide to participate and later change your mind, you are free to stop participation 
at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or 
the quality of health care that you receive at this center. 
 
How many people will take part in this study? 
About 30 people (15 with high blood pressure and normal aldosterone level, 15 with 
high blood pressure and high aldosterone level) will take part in this study at UT 
Southwestern or Parkland Health & Health System.   
 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this consent 
form and will have the following tests and procedures.  Some of the procedures may be 
part of your standard medical care, but others are being done solely for the purpose of 
this study. 
 
 
Screening Procedures 
To help decide if you qualify to be in this study, you will have the following tests 
and/or evaluations. 
 
 Physical exam, medical and surgical history, history of mental illness, and 
substance abuse; 
 Vital signs; 
 Blood tests; 
 Demographic information (age, sex, ethnic origin) 
 Pregnancy testing (urine test for female only) 
 Research Personnel will provide diet containing approximately 2 grams of 
sodium per day for 7 days. 
 If you are taking medications for high blood pressure, you will be asked to 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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Page 3 of 13 
 
 
 
 
 
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stop your medications for 1 week.  
 One week after you stop your medications and take 2-gram sodium diet we 
have provided, you will be asked to come our laboratory. 
 
Group Assignment  
If the researchers believe you can take part in this study, you will be asked to take 
Amlodipine or Eplerenone. You may receive Amlodipine or Eplerenone first. Then, 
taking study drugs for 8 weeks you will be asked to stop the first drug and start the 
second drug for 8 weeks. The order of the treatment is in random order. The study 
assignment is made in advance by a process similar to flipping a coin. You have a 1 
in 2 chance of receiving Amlodipine or Eplerenone first. 
 
The group you will be in is decided by Investigation drug service at the University of 
Texas Southwestern Medical Center.  Neither you nor the researchers will be 
allowed to choose which group you are assigned to. 
 
Neither you nor the researchers will know which group you are in.  However, the 
sponsor will release the information about your assignment to the researchers if it is 
needed for your safety. 
 
Study Medication/Intervention 
 
If you decide to participate in this study you will be asked to either: 
 
 Take Amlodipine 1 tablet once a day for 8 weeks first, then stop 
Eplerenone 1 tablet once a day for 8 weeks. 
OR 
 Take Eplerenone 1 tablet once a day for 8 weeks first, then take 
Amlodipine 1 tablet once a day for 8 weeks. 
 
Procedures and Evaluations during the Research 
 
Visit 1 (At 0 week; 4 hours), 
 
 You will be asked to collect urine for 24 hours to check sodium in urine the 
day before the first visit while you consume 2-gram sodium diet. 
 You will be asked to do a questionnaire to assess your dietary intake. 
 
 When you return urine samples, research personnel will place a thin plastic 
tube in a vein in your arm. 
 Research personnel will collect four tablespoons of blood from the tube in 
your arm for the research purpose. 
 You will have an electrocardiogram (ECG) to measure electrical activity in the 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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heart. 
 An arm cuff will be placed on the upper arm to measure your blood pressure. 
 A tiny needle will be placed in a nerve in your right leg to measure nerve 
signals. 
 You will have a sonogram on your arm to measure blood flow in your arm 
 You will have 2 sticky patches placed on the same arm to measure muscle 
activity or electromyogram (EMG) during arm exercise. 
 Research personnel will strap one of your hands to a bicycle pedal and move 
the other arm pedal to move your arm in circle while you keep your arm 
muscle completely relaxed for 5 minutes. 
 Then, you will be asked to move your hand on the pedal in circle without 
assistance from research personnel for 5 minutes. 
 After waiting for your nerve activity and blood pressure to return to normal for 
30 minutes, you will be asked to do handgrip exercise intermittently at the rate 
of 20 times per minute at 30 % and 45% of your maximal strength each for 3 
minutes while we monitor your blood pressure, your nerve activity, muscle 
activity, and blood flow in your arm.  
 After waiting for your nerve activity and blood pressure to return to normal for 
30 minutes, you will be asked to use your hand to hold a handgrip bar 
constantly without relaxing your hand at 30 % of your maximal strength for 2 
minutes. 
 Five seconds before you stop exercising, a cuff around your upper arm will be  
inflated to stop blood flow to your arm for 2 minutes.  
 After the cuff is released, we will continue to monitor your nerve activity, and 
blood flow in your arm for 5 minutes. 
 After waiting for your nerve activity and blood pressure to return to normal for 
30 minutes, you will be asked to put your hand in iced water for 2 minutes, 
while we monitor your blood pressure, your nerve activity, and blood flow in 
your arm. 
 You will then be started on the first study drug (Amlodipine or Eplerenone) 
 
Visit 2: (2 weeks later:30 minutes) 
 Two weeks after you start the first study drug, research personnel will check 
your blood pressure and adjust your medications according to your blood 
pressure.      
 
Visit 3: (2 weeks later:30 minutes) 
 Four weeks after you start the first study drug, research personnel will check 
your blood pressure and adjust your medications according to your blood 
pressure.  
 
Visit 4: (2 weeks later:30 minutes) 
 Six weeks after you start the first study drug, research personnel will check 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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your blood pressure and adjust your medications according to your blood 
pressure.      
 
 Visit 5: (2 weeks later:30 minutes) 
 You will be asked to stop your BP medications and take diet containing 
approximately 2 grams of sodium per day for 7 days before the study 
 You will be asked to collect urine for 24 hours to check sodium in urine the 
day before the second study while you consume 2-gram sodium diet. 
 When you return urine samples, research personnel will collect four 
tablespoons of blood from the tube in your arm for the research purpose. 
 The same procedure in visit 1, will be repeated.  
 You will then be started on the second study drug (Eplerenone or 
Amlodipine). 
 
Visit 6: (2 weeks later:30 minutes) 
 Two weeks after you start the second study drug, research personnel will 
check your blood pressure and adjust your medications according to your 
blood pressure.      
 
Visit 7: (2 weeks later:30 minutes) 
 Four weeks after you start the second study drug, research personnel will 
check your blood pressure and adjust your medications according to your 
blood pressure.  
 
Visit 8: (2 weeks later:30 minutes) 
 Six weeks after you start the second study drug, research personnel will 
check your blood pressure and adjust your medications according to your 
blood pressure.      
 
Visit 9: (2 weeks later:4 hours) 
 You will be asked to stop your BP medications and take diet containing 
approximately 2 grams of sodium per day for 7 days before the study 
 You will be asked to collect urine for 24 hours to check sodium in urine the 
day before the second study while you consume 2-gram sodium diet. 
 When you return urine samples, research personnel will collect four 
tablespoons of blood from the tube in your arm for the research purpose. 
 The same procedure in visit 1, will be repeated.  
 End of study. 
 
 
 In a separate optional visit, you will be asked to pedal on a stationary bicycle. 
It will become harder to pedal the longer you exercise. You will breath into a 
mouthpiece (like a snorkel) or a facemask so we can measure the air you 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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breathe. You will be connected to an EKG and blood pressure monitor and 
will be monitored during the test. This will help us ensure you are safe and 
study how the heart responds to exercise and determine your exercise 
capacity. During the second half of the test, an echocardiogram will be 
performed while you are pedaling on a reclining bike. 
 
 
The blood tests and blood flow tests done in this study are designed for research, not 
for medical purposes.  They are not useful for finding problems or diseases.  Even 
though the researchers are not looking at your blood tests and blood flow tests to find or 
treat a medical problem, you will be told if they notice something unusual.  You and your 
regular doctor can decide together whether to follow up with more tests or treatment.  
Because the blood tests and blood flow tests done in this study are not for medical 
purposes, the research results will not be sent to you or to your regular doctor.  
 
How long can I expect to be in this study? 
The study will last for approximately 16 weeks. Visits 1 and 9 will require 4 hours of your 
time and visits 2 to 8 will requires 30 minutes of your time at each visit. There will be no 
follow-up visit after the end of study.  
 
You can choose to stop participating for any reason at any time.  However, if you decide 
to stop participating in the study, we encourage you to tell the researchers.  You may be 
asked if you are willing to complete some study termination tests. 
 
What are the risks of the study? 
 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side effects. 
You should discuss these with the researchers and your regular health care provider.  
-Eplerenone may cause some, all or none of the side-effects listed below. 
  
 
Frequent 
30% of subjects 
Occasional 
Less than 5% of subjects 
Rare 
Less than 1% of subjects 
Serious 
 
High potassium 
Allergic reaction 
Less Serious 
 
Dizziness, fatigue 
Low blood pressure,  
Minor 
 
 
 
 
- Amlodipine may cause some, all or none of the side-effects listed below. 
 
 
Frequent 
30% of subjects 
Occasional 
Less than15% of subjects 
Rare 
Less than 1% of subjects 
Serious 
 
 
Allergic reaction 
Less Serious 
 
Swelling of the feet, 
constipation, 
Low blood pressure, 
dizziness 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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headache, elevated 
heart rate, heart 
pounding 
Minor 
 
 
Increase in size of the 
gums  
 
-Placement of a needle in a nerve: One out of ten may have  muscles soreness, pins-
and-needles feeling , increased sensitivity to touch, leg or arm numbness or weakness 
one or two days after the experiment.  However, these symptoms usually resolve within 
2-3 weeks after the procedure. We will ask you not to exercise your arm or leg within 24 
hours after procedure. Permanent damage to the nerve has not been reported to occur 
from this procedure. 
 
-Blood pressure cuff inflation: The blood pressure cuff will squeeze your arm tightly. 
However, any discomfort will stop as soon as the pressure in the cuff is released. 
 
-Placement of a thin tube in a vein: You may experience discomfort, bleeding, and/or 
bruising.  You may feel dizzy or faint.  On a rare occasion, an infection may develop at 
the site where the tube was placed. There is a small risk that a blood clot will form or the 
thin plastic tube (catheter) will break. 
 
-Blood samples: You may experience discomfort, bleeding, and/or bruising.  You may 
feel dizzy or faint.  On a rare occasion, an infection may develop at the site where the 
blood was collected.   
 
-Handgrip exercise: You may experience discomfort or aching in your arm but the 
sensation should stop quickly after you stop exercise. 
 
-Cardiopulmonary testing: With any type of exercise testing, there exists the 
possibility of injury or discomfort. Hard exercise may cause strain or injury to the 
muscles, bones and joints. During testing, the risk of having a heart attack or even dying 
goes up slightly, however the risk during any given session in an apparently healthy 
person is less than 1/100,000 tests. Exercise tests may also occasionally be 
accompanied by abnormal blood pressure, nausea, fainting, muscle soreness, joint and 
bone injury, and in rare instances, heart attack, stroke, or death. Every precaution will 
be taken to minimize these risks by evaluating your health and fitness status throughout 
the study. A licensed physician will be immediately available. 
 
 
 
 
Yes, I agree to have the optional cardiopulmonary testing during this study. 
                                Initials                     Date  
Patient 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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No, I do not agree to have the optional cardiopulmonary testing during this study. 
                                Initials                     Date  
Patient 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this cannot be 
guaranteed.  
 
 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort and/or 
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although 
unlikely. 
 
You will have 14 tablespoons of blood collected because you are in this research study. 
 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the researchers. 
 
How will risks be minimized or prevented?   
The research laboratory is fully equipped to handle any bad side effects. Dr. 
Vongpatanasin is a high blood pressure specialist and cardiologist with extensive 
experiences in performing the research procedures in this study. Your heart rate, 
electrocardiogram, and blood pressure will be monitored constantly during the study. 
Emergency equipment, in the event of that your heart stops or you stop breathing, is 
immediately available with highly trained staff. 
 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Tell the researchers before you take any new medication, even if it is prescribed 
by another doctor for a different medical problem or something purchased over 
the counter. 
 Tell your regular doctor about your participation in this study. 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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 Report to the researchers any injury or illnesses while you are on study even if 
you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes.  You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is important 
to your health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, 
you should report them to the researchers right away.  Telephone numbers where they 
can be reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone 
number in your area).  Tell emergency personnel about any medications you are taking, 
including any medications you are taking for this study.   
 
What are the possible benefits of this study? 
 
If you agree to take part in this study, there will not be direct benefits to you.  The 
researchers cannot guarantee that you will benefit from participation in this research. 
 
We hope the information learned from this study will benefit others with high blood 
pressure in the future.  Information gained from this research could lead to better 
treatment of high blood pressure during exercise.   
 
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for high blood pressure. 
Instead of being in this study, you can receive high blood pressure treatment from your 
regular doctor. 
 
Will I be paid if I take part in this research study? 
Yes.   
 
You will be paid $ 1,000 for participation in completing the entire study. However, if you 
stop taking part in this study or are withdrawn by the research team, you will paid 
according to number of weeks participated the study of $ 60 per week. Your Social 
Security Number (SSN) will be given to The University of Texas Southwestern Medical 
Center in order to process your payment as required by law. This information will remain 
confidential unless you give your permission to share it with others, or if we are required 
by law to release it. 
 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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There are no funds available to pay for parking expenses, transportation to and from the 
research center, lost time away from work and other activities, lost wages, or child care 
expenses. 
 
If you are an employee of UT Southwestern, your payment will be added to your regular 
paycheck and income tax will be deducted. 
 
UT Southwestern, as a State agency, will not be able to make any payments to you for 
your participation in this research if the State Comptroller has issued a “hold” on all 
State payments to you.  Such a “hold” could result from your failure to make child 
support payments or pay student loans, etc.  If this happens, UT Southwestern will be 
able to pay you for your taking part in this research 1) after you have made the 
outstanding payments and 2) the State Comptroller has issued a release of the “hold.” 
 
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done only for 
this research study (i.e., the Screening Procedures, Experimental Procedures, or 
Monitoring/Follow-up Procedures described above).   
 
However, the standard medical care for your condition (care you would have received 
whether or not you were in this study) is your responsibility (or the responsibility of your 
insurance provider or governmental program).  You will be charged, in the standard 
manner, for any procedures performed for your standard medical care. 
 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the top 
of this form immediately. 
 
Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas or  
Parkland Health & Hospital System. 
 
You retain your legal rights during your participation in this research 
 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop taking 
part in the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship 
with the UT Southwestern staff or doctors.  Whether you participate or not will have no 
effect on your legal rights or the quality of your health care. 
 
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If you are a medical student, fellow, faculty, or staff at the Medical Center, your status 
will not be affected in any way. 
 
Your doctor is a research investigator in this study.  S/he is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss your 
care with another doctor who is not part of this research study.  You do not have to take 
part in any research study offered by your doctor. 
 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem becomes worse. 
 The researchers believe that participation in the research is no longer safe for 
you. 
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s instructions. 
 
 
Will my information be kept confidential? 
 
Information about you that is collected for this research study will remain confidential 
unless you give your permission to share it with others, or as described below.  You 
should know that certain organizations that may look at and/or copy your medical 
records for research, quality assurance, and data analysis include: 
 
• 
National Institute of Health 
• 
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people; and 
• 
The UT Southwestern Institutional Review Board.  
• 
Quest Diagnostic Laboratory 
 
A description of this clinical trial will be available on http://www.trials.gov, as required by  
U.S. law. This web site will not include information that can identify you. At most, the 
Web site will include a summary of the results. You can search the Web site at any 
time.  In addition to this consent form, you will be asked to sign an "Authorization for 
Use and Disclosure of Protected Health Information."  This authorization will give more 
details about how your information will be used for this research study, and who may 
see and/or get copies of your information. 
 
Whom do I call if I have questions or problems? 
For questions about the study, contact Dr. Vongpatanasin at 214-648-2103 during 
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regular business hours and at 214-645-8424 after hours and on weekends and 
holidays.   
 
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
Your signature below certifies the following: 
 
• You have read (or been read) the information provided above. 
• You have received answers to all of your questions and have been told who to call 
if you have any more questions. 
Study ID: STU 072012-066   Date Approved: 6/7/2019


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• You have freely decided to participate in this research. 
You understand that a copy of this signed consent document, information about this 
study and the results of any test or procedure done may be included in your 
medical record and this information may be available to health care providers, and 
authorized persons including your insurance company. 
• You understand that you are not giving up any of your legal rights. 
 
 
__________________________________________________ 
Participant’s Name (printed) 
 
 
__________________________________________________ 
Participant’s Signature 
 
_________AM/PM 
Date         Time 
__________________________________________________ 
Name of person obtaining consent (printed) 
 
 
__________________________________________________ 
Signature of person obtaining consent 
 
_______AM/PM 
Date       Time 
 
 
INTERPRETER STATEMENT: 
I have interpreted this consent form into a language understandable to the participant and the participant 
has agreed to participate as indicated by their signature on the associated short form. 
 
 
 
 
 
 
 
 
 
 
 
Signature of Interpreter 
 
Printed Name of Interpreter 
 
Date 
 
Time 
 
AM/PM 
 
 
Study ID: STU 072012-066   Date Approved: 6/7/2019