Conditions: Autonomic Nervous System Diseases Orthostatic Hypotension Dopamine Beta-Hydroxylase Deficiency Orthostatic Intolerance
Keywords: autonomic nervous system diseases blood pressure congenital orthostasis catecholamines
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this study is to try different medications in patients with low blood pressure and other problems with their involuntary (autonomic) nervous system. The pharmacological trials in this study will perhaps lead to more effective treatment. The protocol includes single dose trials, dose-selection trials, 5-day trials and chronic (approximately 2 months) trials, although only dose-selection trials were consistently performed and have results presented.

Detailed description:
We see many patients at the Autonomic Dysfunction Center who can be given a fairly definitive diagnosis, e.g., Orthostatic Intolerance, Pure Autonomic Failure, Multiple System Atrophy, and Baroreflex Failure. However, some patients present with a unique constellation of symptoms of autonomic dysfunction so that they do not fit into a diagnostic category. We hypothesize that a genetic cause exists in some of these patients. We further propose that our comprehensive evaluation of these patients will provide us with information on the pathophysiology of their condition and assist us in optimizing their treatment.

Arms:
arm 1: Patients with known or suspected Dopamine beta-Hydroxylase Deficiency were administered Droxidopa doses of 25 mg, 50 mg, 100 mg, 200 mg, 250 mg or 300 mg up to three times daily. Supine and upright blood pressures were subsequently measured 60 to 240 minutes post-dose.

Interventions: intervention 1: Droxidopa Oral Product
Intervention descriptions: intervention 1: Droxidopa administered in increasing dosages up to 300 mg

Protocol document:
Prot_SAP_000.pdf: 
April 4, 2002 
 
 
 
Treatment of Orthostatic Hypotension 
 
NCT00581477 
 
Protocol and Statistical Analysis Plan 
 
November 14, 2003 


 
2
CLINICAL RESEARCH CENTER 
VANDERBILT UNIVERSITY 
PROJECT PROPOSAL #1288 
 
 
Project Title: The Treatment of Orthostatic Hypotension  
The Treatment of Orthostatic Hypotension 
 
Project Number:   
 
 
 
IRB Approval Number:  030750 
 
IRB Approval Date: November 14, 2003  
 
Principal Investigator: 
David Robertson, M.D., Professor of Medicine, Pharmacology and  
Neurology  
 
Co-Investigator(s): 
 
Emily Garland, Ph.D., Division of Clinical Pharmacology 
 
 
 
 
Paula Yamhure, RN, Division of Cardiology 
 
 
 
 
Italo Biaggioni, MD, Departments of Medicine and Pharmacology 
 
 
 
 
Satish Raj, MD, Division of Clinical Pharmacology 
 
 
 
 
Bonnie Black, RN, Division of Cardiology 
 
 
 
 
Indu Taneja, MD, Division of Clinical Pharmacology 
 
HYPOTHESIS 
We propose that a systematic trial of medications in patients presenting with a unique and chronic 
constellation of symptoms of autonomic dysfunction will provide us with information on the 
pathophysiology of their condition and assist us in optimizing their treatment. 
 
SPECIFIC AIMS 
To give a single dose of one or more drugs to determine the effect on orthostatic hypotension in a group 
of patients with autonomic dysfunction of unknown pathophysiology.  Depending on the results of these 
single-dose trials, we might subsequently do 5-day trials and chronic (approximately 2 months) trials. 
 
 
BACKGROUND AND SIGNIFICANCE 
Norepinephrine (NE) and epinephrine (E) are critical determinants of blood pressure. Moreover, they are 
also involved in the regulation of autonomic outflow in the brainstem and spinal cord. In the periphery, 
NE is pressor, but within the central nervous system (CNS) it often depresses sympathetic outflow, 
resulting in a fall in blood pressure.  Thus, any factor that alters the synthesis of these catecholamines 
can perturb blood pressure at several interacting levels. Tyrosine hydroxylase [(tyrosine to L-
dihydroxyphenylalanine (DOPA)] is the rate-limiting step in NE synthesis under almost all 
circumstances. DOPA decarboxylase converts DOPA to dopamine (DA).  Dopamine-ß-hydroxylase 
(DBH) converts DA to NE.  Loss of DBH leads to an inability of the neuron to synthesize NE, resulting 
in a buildup of DA.   
 
In 1986, we, and independently, colleagues in Rotterdam, reported a syndrome in which patients have a 
congenital absence of the DBH enzyme. Results of a battery of biochemical and physiological tests in 
DBH-deficient patients helped us to identify the pathophysiology of these patients and enabled us to 
design an effective treatment. 
 
Occasionally, patients present to the Autonomic Dysfunction Center with a unique constellation of 


 
3
symptoms of autonomic dysfunction so that they do not fit into a diagnostic category (Orthostatic 
Intolerance, Pure Autonomic Failure, Multiple System Atrophy, Baroreflex Failure).  Some of these 
patients have severe orthostatic hypotension and resemble those with DBH deficiency, but they do not 
have the extreme plasma levels of DA.  We propose that medication trials in these patients will assist us 
in optimizing their treatment.  Evaluation will be undertaken under controlled conditions with 
medication and dietary restrictions and will consist primarily of orthostatic blood pressure and heart rate 
measurements and plasma catecholamine determinations. 
 
Participants will first take part in a study designed to provide information on the pathophysiology of 
their autonomic problems (The Pathophysiology of Orthostatic Hypotension, IRB#030752, CRC 
approval pending).  Results from this study will help us determine which drug(s) to administer in the 
proposed protocol. 
 
PRELIMINARY STUDIES 
Once the pathophysiology of DBH deficiency was understood, we were able to rapidly develop a 
specific and effective therapy. Consistent with DOPA and DA reducing blood pressure, the 
administration of a tyrosine hydroxylase inhibitor, such as metyrosine, raises blood pressure in DBH-
deficient individuals. The pressor effect appears to correlate with the metyrosine-associated reduction in 
plasma DA and DOPA levels and also urinary DA levels. DOPS, or Droxidopa INN:(-)-threo-3-(3, 4-
dihydroxyphenyl)-L-serine, is structurally closely related to NE, but has an additional COOH group.  It 
can be pumped up into the noradrenergic nerves and converted into NE by L-aromatic amino-acid 
decarboxylase without requiring DBH.  L-DOPS has been used effectively in the treatment of patients 
with complete DBH deficiency.  It might also improve the blood pressure in patients that have profound 
orthostatic hypotension but do not appear to have complete DBH deficiency.   
 
EXPERIMENTAL DESIGN AND METHODS 
Participants in this study are patients with hypotension, who have undergone evaluation as part of our 
“The Pathophysiology of Orthostatic Hypotension” protocol (IRB#030752, CRC approval pending).  
Based on the results of these studies, we will administer medication which we believe might improve 
their symptoms.  We will first test a single dose of one or more drugs with monitoring for 24 hours.  A 
drug or drugs effective at preventing an orthostatic fall in blood pressure might then be tested in a 5-day 
crossover trial with comparison of effects to placebo.  Based on the results of the 5-day trial, a patient 
might then be given a 2-month trial of the drug, with periodic admissions to the GCRC for assessment of 
symptoms. The period of time needed to complete this study will depend on the number of medications 
tested.   
 
Drug withdrawal 
Participants must remain off any medications that could affect blood pressure for three days prior to and 
during study.  This includes not only their usual scheduled medications, but also other drugs that might 
be taken intermittently. If their symptoms are severe enough that they or their physician have concerns 
that their symptoms may worsen, they may be admitted to the hospital for observation during this 
portion of the study.  While they are an inpatient on the GCRC, their general condition, blood pressure 
and heart rate will be checked regularly to reduce any risk. 
 
Urine pregnancy test 
We will perform a urine pregnancy test every time female participants are admitted to the hospital for 
this study.   
 
Diet 


 
4
We will ask study participants to eat a standard diet with no caffeine, 150-mEq/day sodium, 70 mEq 
potassium, and no substances that interfere with catecholamine synthesis, release or assay for three days 
prior to and during testing. 
 
24-Hour Urine Collection 
Participants will collect their urine for 24 hours every time they are admitted to the hospital for this 
study. The urine will be analyzed for sodium, potassium, creatinine,and  catecholamines. 
 
Orthostatic vital signs 
Orthostatic vital signs will be measured several times a day.  This testing consists of blood pressure and 
heart rate measured while patients are lying down and then repeated after standing quietly for 5 minutes, 
using the Dinamap. 
 
Single-dose drug trials 
Participants will be admitted to the Vanderbilt Clinical Research Center the evening prior to the study. 
In the morning, the patients will be seated or in bed for a 30 min baseline period of blood pressure and 
heart rate monitoring.  The medication will be given by mouth, and blood pressure and heart rate will be 
monitored every 10-15 minutes for the first hour, using a Dinamap. Orthostatic vital signs will be taken 
after 1, 2, 3, 4, 8, and 12 hours.  Fifteen ml of blood will be collected through a saline lock during 
baseline and after 2, 4, and 8 hours while in the supine and standing positions to measure 
catecholamines (total of 4 samples lying down and 4 samples upright).  Aldosterone will also be 
measured in blood collected during baseline and at one other timepoint, depending on the duration of the 
drug effect (total of 2 samples lying down and 2 samples upright). A second blood sample will be 
collected with the aldosterone and an aliquot of plasma frozen for possible analysis of plasma renin 
activity. Urine will be collected from 0-7 hours, 7-12 hours and 12-24 hours for measurement of 
catecholamines.  Depending on how well the drug is tolerated and the degree of improvement in 
orthostatic vital signs and symptoms following the drug, another single-dose drug trial might be 
scheduled 48 hours after the first or the patient might be asked to start a 5-day trial of the drug at that 
time.   If they are not scheduled for another trial at this time, they can be discharged.  The medications 
include domperidone, metyrosine, L-DOPS, alpha-methyldopa, L-dopa, carbidopa, atomoxetine, and 
placebo.   
 
 
 
 
 
Single-dose trial 
Time 
Days 3,2  
pre-study 
Day 
1 
pre-study 
                                   Study Day  
 
 
 
0 hr 
1 hr 
2 hr 3 hr 4 hr 8 hr 12 
hr 
24 
hr 
Drug/diet 
restriction 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission 
to 
GCRC 
 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
Drug 
administration 
 
 
X 
 
 
 
 
 
 
 
Blood sample 
 
 
X 
 
 
 
X 
X 
X 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
5-Day drug trials 
Once the appropriate dose has been decided, we will conduct a single-blinded crossover trial.  
Depending on where they live and the severity of their symptoms, participants might be able to go home 


 
5
for part of this study.  However, after 4 days on the drug (or placebo), they will be admitted to the 
GCRC.  They will be supine and NPO after midnight.  In the morning, we will do a Posture Study to 
determine the effectiveness of the treatment.  Before breakfast, we will draw 15 ml of blood while they 
are supine and another 15 ml after they have stood for 30 minutes to measure catecholamines and 
aldosterone.  A second blood sample will be collected with the aldosterone and an aliquot of plasma 
frozen for possible analysis of plasma renin activity. We will monitor blood pressure and heart rate 
during this study, using a Dinamap. Standing time will be determined, and the participants will be asked 
about their symptoms periodically during the study.  For at least three days following this testing, 
participants will take no medication.  They will then start a 5-day regimen of the medication, if they 
previously took the placebo, or placebo, if they previously took the medication. They will not be told 
whether they are taking active drug or placebo.  The Posture Study will be repeated in the GCRC after 
the second 5-day period.   
 
 
 
 
 
 
 
 
5-day trial 
Time 
Day 
3  
pre-
study 
Days 
1,2 
pre-
study 
Study 
day 0   
Study 
days 
1,2,3 
Study 
day 4 
Study 
day 5 
Study 
days 
6,7 
Study 
day 8 
Study days 
9,10,11 
Study day 
12 
Study day 
13 
Drug/diet 
restriction 
X 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
Urine 
collection 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Admission to 
GCRC 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/placebo 
administration 
 
 
X 
X X X X 
 
 
 
X 
X 
X X 
X 
 
Posture 
study/Blood 
sample 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Vital signs 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Depending on the results of the 5-day trial, participants will be given a longterm trial of a drug.  At the 
initiation of treatment, and after two weeks, four weeks, and eight weeks of drug, they will be evaluated 
by a posture study, 24-hour urine collection and assessment of their symptoms.  The dose of the 
medication will be adjusted after two and four weeks of treatment if there has been insufficient 
improvement in blood pressure (able to stand with< 20 mmHg decrease in systolic blood pressure) or 
symptoms.   
 
 
 
 
 
 
Chronic trial 
Days 
-3,-2 
-1 
0 
1-10 
11,12 
13 
14 
15-24 25,26 
27 
28 
29-52 
53,54 
55 
56 
Restrict diet 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Collect urine   
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Admit 
to 
GCRC 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy 
test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Take Drug  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Posture 
study/ Collect 
blood 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signs 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Adjust 
dosage 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 


 
6
 
 
BIOSTATISTICS 
Statistical analyses will be performed on a personal computer with the statistical package SPSS for 
Windows (Version 10.0, SPSS, Chicago). Some paired comparisons (Paired t-test, Wilcoxon signed-
rank test, repeated measures ANOVA, Friedman ANOVA by ranks) might be needed to compare 
treatment responses within a subject. 
 
Protection of Human Subjects: 
   
POPULATION:   
The conduct of these studies will involve approximately 25 human subjects. Subjects will include 
patients with severe orthostatic hypotension and other autonomic symptoms who do not meet criteria for 
one of our standard diagnoses.  Potential study participants will first take part in “The Pathophysiology 
of Orthostatic Hypotension” (IRB #030752, CRC approval pending). Results from that study will 
provide information on the pathophysiology of the autonomic disorder and might suggest which 
medication(s) might be an effective treatment. Subjects will range in age from 18-70 and be non-
smokers, drug-free, able to give informed consent, and free of pulmonary, renal, hematopoietic, hepatic 
and cardiac disease.  Exclusion criteria for the study include smoking, pregnancy, medications affecting 
the autonomic nervous system, any chronic illness, and anemia (Hct<35). 
 
RESEARCH MATERIALS:  
Research materials include blood, urine, and data.  The blood will be analyzed for catecholamines, renin 
and aldosterone. Urine will be analyzed for catecholamines, sodium, potassium, and creatinine.  
 
RECRUITMENT OF SUBJECTS:  
We will recruit patients from those referred to the physicians of the Autonomic Dysfunction Center at 
Vanderbilt who have participated in “The Pathophysiology of Orthostatic Hypotension” (IRB #030752, 
CRC approval pending). In each instance, the investigator will describe the complete protocol to the 
prospective participant.  The subjects will then be given a written informed consent form that has been 
approved by the Vanderbilt Institutional Review Board.  The subject will be given adequate time to read 
the consent form, ask questions, and if satisfied by the responses, sign the form.  Consent or refusal to 
participate in this study will not affect medical care.  No modifications or waiver of the elements of 
consent have been authorized, nor will any be necessary in the execution of this study. 
 
POTENTIAL RISKS:   
Blood drawing and insertion of venous catheters are uncomfortable and may cause bruising, bleeding, 
permanent damage to the vessel and in rare instance, infection.  The risk of bleeding can be prevented by 
tight compression of the site.  Experienced personnel will place all intravascular lines using sterile 
technique.   
 
Consuming a sodium- and caffeine-controlled diet might not be to the subject’s taste preferences. If a 
subject drinks caffeinated beverages regularly and stops caffeine intake suddenly, he/she might have 
headaches and fatigue for a few days.  These symptoms can be avoided by cutting down gradually on 
the amount of caffeine in the diet. 
 
Stopping medications might cause a temporary worsening of symptoms for patients.  Careful monitoring 
of blood pressure and heart rate will permit immediate attention and termination of the protocol when 
necessary. 
 
Collection of urine can be inconvenient. 


 
7
 
The seated oral medical trials are tedious and boring because they require being seated for an extended 
period of time while blood pressure is monitored.     
 
When any medication is used in testing, there is a small risk of an unforeseeable life-threatening allergic 
reaction.  Side effects associated with specific medications are listed below.  Side effects are listed as 
common, uncommon, and rare.   
 
Domperidone – common: dry mouth, abdominal cramps, diarrhea. Uncommon: loss of balance 
or muscle control, swelling of mouth, increased breast milk flow, headache, hives, hot flashes. 
Rare: pounding or racing heart beat, swelling of extremities, change in appetite, constipation, 
dizziness. 
 
-Methyldopa – common: weakness, distention of lower abdomen, constipation, swelling of the 
lower extremities, fever and depression, anxiety, nightmares, being sleepy or drowsy, headache 
and dry mouth.  Uncommon:  dizziness, gas, diarrhea, chest pain, stuffiness of the nose, low 
blood pressure on standing, low heart rate, nausea or vomiting, abnormal liver function tests.  
Serious or life-threatening: extremely rare reactions are fatal liver damage and fatal inflammation 
to the heart. 
 
Carbidopa – only reported to have adverse effects when it is given with the drug levodopa for 
Parkinson’ s disease.  Common adverse events with the carbidopa-levodopa combination include 
dyskinesias and nausea.  Less common adverse effects are psychotic episodes, depression and 
dementia. 
 
Metyrosine – common: drowsiness, diarrhea, drooling, trembling and shaking of hands and 
fingers; trouble speaking. Uncommon: decreased sexual ability in men, dry mouth, nausea, 
vomiting, stuffy nose, anxiety, confusion, hallucinations, mental depression.  Rare or life-
threatening: crystalluria (the excretion of crystals in the urine resulting in urine retention), black, 
tarry stools, unusual bleeding or bruising, muscle spasms, painful urination, pinpoint red spots on 
skin, restlessness, shortness of breath, shuffling walk, skin rash and itching, swelling of feet or 
lower legs, tic-like movements 
 
L-Dopa (levodopa) – common: abdominal pain, dry mouth, loss of appetite, nightmares, gas, 
abnormal thoughts, agitation, anxiety, clumsiness, difficulty swallowing, dizziness, excessive 
watering of mouth, nausea and vomiting, uncontrolled body movements.  Uncommon: Chest 
pain, mood or mental changes, discoloration of sweat or urine, constipation, diarrhea, flushed 
skin, headache, hiccups, increased sweating, muscle twitching, trouble sleeping, blurred vision, 
difficult urination, dilated pupils, dizziness or lightheadedness when getting up from a lying or 
sitting position, double vision, fast or pounding heartbeat, hot flushes, mental depression, skin 
rash, weight gain or loss. Rare: back or leg pain, black tarry stools, chills, convulsions, fever, 
high blood pressure, loss of appetite, swelling of feet or lower legs 
 
Atomoxetine – common: headache, nausea, sleepiness, trouble sleeping, anxiety, dry mouth, loss 
of appetite, dizziness, constipation, flushed or warm sensation, rash. Uncommon: loose stools, 
excessive energy, excitement, stomache ache, fluttering sensation in chest, abnormal heart 
rhythm sensations, tingling, vomiting, aching muscles. Rare: abnormal blood tests, such as 
abnormal liver function tests 
 
L-DOPS – The use of L-DOPS is under investigation and is not approved by the FDA.  We have 
used it for many years in a small population of patients that lack dopamine-beta-hydroxylase, the 


 
8
enzyme that converts dopamine to norepinephrine.  The initial dose is low and adjusted to treat 
low blood pressure without adverse effects.  It is possible that there may be some side effects.  
The following rare side effects have been reported: increased blood pressure, nausea, headache, 
hallucination, anorexia, increased liver enzymes, dizziness/lightheadedness, heart fluttering, 
thirst, nervousness, stomachache, vomiting, abdominal pain, chest pain, and fatigue. 
 
Placebo – The placebo is a pill or capsule that does not contain active ingredient.  It should 
therefore have no side effects. 
 
 
PROTECTION:  
Monitoring of vital signs will help minimize potential risks.  All information will be kept strictly 
confidential. 
 
BENEFITS:  
We guarantee no direct benefits to the study participants.  Results of this study will improve our 
understanding of autonomic dysfunction and might lead to important advances in the management of 
these diseases. 
 
DATA SAFETY MONITORING PLAN 
Data from subjects enrolled in this study will be reviewed on a bi-monthly basis by the P.I.and at least 
one co-investigator. Any adverse event of a serious or greater nature will be reviewed immediately with 
the P.I.  Emily Garland, Ph.D. will be responsible for tracking adverse events in this study. 
 
The adverse event will be described with the following information: description of the event; outcome of 
the event; duration of the event; relationship to study procedure; requirement, if any, for treatment or 
intervention; and outcome. 
 
Adverse events will be graded according to the following scale: 
 
0 = No adverse event or within normal limits 
 
1 = Mild adverse event (transient and mild in nature, and no treatment is necessary) 
2 = Moderate adverse event (some intervention and treatment are necessary, but participant 
completely recovers 
3 = Severe adverse event (an event that results in hospitalization, disability, or death or is life-
threatening) 
 
The investigator will state his opinion on whether there is a reasonable possibility that the event or 
experience is related to a procedure performed as part of this study. 


 
9
JUSTIFICATION FOR GCRC UTILIZATION  
 
The following GCRC services are necessary for conducting this scientific study: 
 
Inpatient/Outpatient Support:Approximately 25 patients will be studied over the five years.  The length 
of stay and number of admissions will depend on the number of medication trials performed with each 
patient. A research  nurse will be needed to draw blood  and monitor blood pressure during 
pharmacological testing, to document pulse and blood pressure during orthostatic vital signs, to perform 
posture studies, and to assist with urine collections, as well as for general patient care. 
 
Biostatistical Support: Although we do not anticipate doing any data analysis, review by the GCRC 
biostatistician is requested, as well as assistance with any unforeseen data analysis. 
 
Informatics Support: Review by the Informatics specialist and access to data from the Core Lab is 
required. 
 
Core Lab Utilization: The Core Lab is needed for plasma and urine catecholamine analysis and urinary 
sodium, potassium and creatinine. 
 
Nursing Support: Nursing support will be needed for blood draws, urine collections, posture studies, and 
medication studies. 
 
Nutrition Services Utilization: We will ask patients to eat a standard diet with no caffeine and 150 mEq 
sodium, 70 mEq potassium while in the hospital for these procedures.  We might ask them to restrict 
their diet for up to three days prior to admission.   
 
 
OTHER SUPPORT 
 
84 urine pregnancy tests are needed. 
700 plasma aldosterone and 50 plasma renin analyses are requested, as well as processing of 650 
aliquots of plasma to be frozen for possible future analysis of plasma renin activity. 


 
10 
Gender/Minority Mix 
 
This study does not exclude research participants by race or gender and includes research participants 
aged 18 – 70 years old.  We expect the overall distribution of participants to be even across gender and 
ethnic groups. 
 
Table I – National Figures for Mix of Study Population 
 
 
Am. 
Indian 
Alaskan  
Native 
Asian 
Pacific  
Islander 
Black, 
of 
H
Origin 
Hispanic White, 
of 
H
Origin 
Other 
Total 
Male 
0.4 
1.4 
5.7 
4.3 
36.9 
* 
48.7 
Female 
0.4 
1.4 
6.0 
4.5 
38.8 
* 
51.1 
Total 
0.8 
2.8 
11.7 
8.8 
75.7 
* 
99.8 
* negligible in this context.        Note: Rounding errors led to totals different from 100%. 
 
 
Table II – Tennessee Figures for Mix of Study Population 
 
 
Am. 
Indian 
Alaskan  
Native 
Asian 
Pacific  
Islander 
Black, 
of 
H
Origin 
Hispanic White, 
of 
H
Origin 
Other 
Total 
Male 
0.1 
0.5 
7.4 
0.4 
39.9 
* 
48.3 
Female 
0.1 
0.5 
8.0 
0.4 
42.8 
* 
51.8 
Total 
0.2 
1.0 
15.4 
0.8 
82.7 
* 
100.1 
* negligible in this context.        Note: Rounding errors led to totals different from 100%. 
 
 
Table III – Anticipated Enrollment – Actual Patient Numbers 
 
Am. 
Indian 
Alaskan  
Native 
Asian 
Pacific  
Islander 
Black, 
of 
H
Origin 
Hispanic White, 
of 
H
Origin 
Other 
Total 
Male 
0 
0 
2 
1 
10 
0 
13 
Female 
0 
0 
2 
0 
10 
0 
12 
Total 
0 
0 
4 
1 
20 
0 
25 
 
 
 
 


 
11 
REFERENCES 
 
Man in 't Veld AJ, Boomsma F, Lenders J, Meiracker Avd, Julien C, Tulen J et al. Patients with 
congenital dopamine b-hydroxylase deficiency. A lesson in catecholamine physiology. Am J Hypertens 
1988;1:231-38. 
Man in 't Veld AJ, Boomsma F, Moleman P, Schalekamp MA. Congenital dopamine-b-hydroxylase 
deficiency: A novel orthostatic syndrome. Lancet 1987;1:183-87. 
Man in 't Veld AJ, Boomsma F, van den Meiracker AH, Julien C, Lenders J, Schalekamp MA. d,l-threo-
3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine 
beta-hydroxylase deficiency. J.Hypertens.Suppl. 1988;6:S547-S549. 
Man in 't Veld AJ, Boomsma F, van den Meiracker AH, Schalekamp MA. Effect of unnatural 
noradrenaline precursor on sympathetic control and orthostatic hypotension in dopamine-beta-
hydroxylase deficiency. Lancet 1987;2:1172-75. 
Robertson D. Genetics and molecular biology of hypotension. Curr Opin Nephrol Hypertens 1994;3:13-
24. 
Robertson D, Biaggioni I, Ertl AC, Robertson RM, Diedrich A, Blakely RD et al. Orthostatic 
intolerance: emerging genetic and environmental etiologies. J.Gravit.Physiol. 1999;6:51-54. 
Robertson D, Goldberg MR, Hollister AS, Onrot J, Wiley R, Thompson JG et al. Isolated failure of 
autonomic noradrenergic neurotransmission: Evidence for impaired beta-hydroxylation of dopamine. 
N.Engl.J.Med. 1986;314:1494-97. 
Robertson D, Haile V, Perry SE, Robertson RM, Phillips JA, Biaggioni I. Dopamine beta-hydroxylase 
deficiency. A genetic disorder of cardiovascular regulation. Hypertension 1991;18:1-8. 
Robertson D, Hale N. Genetic diseases of hypotension. Adv.Pharmacol. 1998;42:61-5.:61-65. 
Robertson D, Hollister AS,  Biaggioni I. Dopamine-b-hydroxylase deficiency and cardiovascular 
control, In: Laragh JH, Brenner BM, editors. Hypertension Pathophysiology, Diagnosis and 
Management. New York: Raven Press, Ltd.; 1990. p. 749-59. 
van den Meiracker AH, Boomsma F, Man in 't Veld AJ. Dopamine-b-Hydroxylase Deficiency, In: 
Robertson D, Low PA, Polinsky RJ, editors. Primer on the Autonomic Nervous System. San Diego, CA: 
Academic Press, Inc.; 1996. p. 205-08. 
 

ICF_001.pdf: 
Treatment of Orthostatic Hypotension
NCT00581477
Informed Consent


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
Revision Date:  12/11/17
Study Title:  The Treatment of Orthostatic Hypotension  
Institution/Hospital: Vanderbilt University 
1 of 7
This informed consent document applies to Adult Patients   (Dose Selection Trial) 
Name of participant: _________________________________________________________ Age: ___________ 
The following is given to you to tell you about this research study.  Please read this form with care and ask any 
questions you may have about this study.  Your questions will be answered.  Also, you will be given a copy of this 
consent form.   
You do not have to be in this research study. You may choose not to be in this study and get other treatments 
without changing your healthcare, services or other rights.  You can stop being in this study at any time.  If we 
learn something new that may affect the risks or benefits of this study, you will be told so that you can decide 
whether or not you still want to be in this study.   You have the right to ask what it will cost you to take part in this 
study. You may wish to contact your insurance company to discuss the costs further before choosing to be in the 
study as there may be added costs that you will be billed for if you agree to be in the study.  You may choose not 
to be in this study if your insurance does not pay for the costs and your doctor will discuss other treatment plans 
with you. 
1.
What is the purpose of the study:
You are being asked to take part in this research study because you have problems with blood pressure
regulation and other symptoms of an impaired involuntary (autonomic) nervous system.  The autonomic nervous
system controls blood pressure, heart rate, the size of your pupils, sweating, and other functions.
Norepinephrine is an important chemical that can raise blood pressure.  Another chemical, dopamine, can lower
blood pressure.  Dopamine can be converted into norepinephrine by a protein called dopamine-beta-hydroxylase
(DBH). The amount of dopamine in your body, compared to the amount of norepinephrine, might be affected by
the activity of DBH and might determine whether you have high, normal or low blood pressure in certain
situations.  You have participated in the study “The Pathophysiology of Orthostatic Hypotension”, and the results
from that study indicate that you might benefit from drugs that modify the level or activity of norepinephrine or
dopamine.  We would now like to treat you with one or more drugs and then do some tests to determine the
effectiveness of the treatments.  You might also be tested after taking an inactive substance (placebo).  The
study is designed to find the best dosage of the drug for you, in terms of safety and effectiveness.  You will
initially be given a low dosage and this will be increased gradually.  Depending on the length of activity of the
drug and its effect on you, you could be given the drug only one time or you could be given it more than one time.
Similarly, you could receive the same dosage of the drug several times or you could receive several different
dosages. You will be given a maximum of four increasing dosages of the drug in one day, and you will take each
drug for a maximum of 7 days.  Depending on the results of these trials, we might subsequently do some longer-
term drug trials for which you will be asked to sign another consent form.
If you agree to participate in this study, the investigators in the Vanderbilt Autonomic Dysfunction Center and 
their collaborators will have access to your medical and research data. 
2.
What will happen and how long will you be in the study?
This study is being conducted at the Vanderbilt Clinical Research Center (CRC) and will take from approximately
1 to 7 days for each drug.   Depending on where you live and the severity of your symptoms, you might be asked
to stay in the hospital for a portion of or the entire study period. One of the investigators will explain the study to
you and ask you to sign this consent form.  The drug that you will take will be marked on the consent form, and
its possible side effects will be discussed with you.  A copy of the consent form will be given to you.
a.
Continued drug withdrawal
You must remain off any medications that could affect blood pressure for three days prior to and during the
study.  This includes not only your usual scheduled medications, but also other drugs that might be taken
intermittently.  If your symptoms are severe enough that you or your physician have concerns that your
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Date of Expiration: 11/20/2020


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
Revision Date:  12/11/17
Study Title:  The Treatment of Orthostatic Hypotension  
Institution/Hospital: Vanderbilt University 
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symptoms may worsen, you may be admitted to the hospital for observation during this portion of the study. 
While you are an inpatient on the CRC, we will check your general condition, blood pressure and heart rate 
regularly to reduce any risk. 
b.
Urine pregnancy test
If you are a female, we will perform a pregnancy test on a sample of your urine prior to the study.  Pregnant
females generally may not participate in research studies because we do not know how pregnancy might
affect the results of the tests.  We might also want to give you some medications that have not been studied in
pregnant women. Very early in pregnancy, a pregnancy test can be negative. Therefore, we advise you to
practice birth control, if you are sexually active, for two weeks before your study starts.
c.
Diet
We will ask you to eat a standard diet with no caffeine and a controlled amount of salt for three days prior to
and during the study.  We will provide this food to you and ask you to eat all of it and no other food.
d.
Drug testing
Medication trials will be started after at least 3 days of medication and diet restriction to assess your response
to a drug that might be beneficial in your treatment.  We will decide which drug to give you based on your
clinical history and the results of testing that you underwent previously.    Before we start drug testing, we will
do a baseline Posture Study (see below) to determine your ability to stand in an unmedicated state.  Blood
pressure and heart rate will be measured with a cuff around your arm every 10 minutes for 30 minutes before
you are given a drug. You will first be given a low dosage of the drug by mouth while you are seated in a chair
or in your bed. Your blood pressure will be measured every 5-15 minutes for one hour after the drug. At 11/2
hours after the first dose each day, you may be asked to lie down for 30 minutes and then sit or stand, if you
are able, for 5 minutes while we measure your blood pressure and collect blood samples to measure
hormones involved in blood pressure control. During this day and following days, you will be given additional
doses of the drug, with the amount of drug given at each time to be determined by your response to the
previous dose.  Before each dose of each drug, blood pressure and heart rate will be measured with a cuff
around your arm every 10 minutes for 30 minutes, and your blood pressure will be measured every 5-15
minutes for one hour after dosing.  Except for the first dose each day, blood pressure will also be measured at
2 hours after the drug, after 5 minutes of lying down and 5 minutes of sitting or standing. You will also be
asked to report any changes in your symptoms and any discomfort you might experience. A Posture Study
may be repeated at the end of the Dose Selection Trial.
e.
24-Hour Urine Collection
You will collect your urine daily for 24 hours. The urine will be analyzed for
□sodium
□hormones that control blood pressure and heart rate.
f.
Posture Study.
You will need to lie in bed for at least 30 minutes with nothing to eat for at least two hours.  A small tube
(catheter) will be placed in your arm vein in order to draw blood.  We will draw two tablespoons of blood while
you are lying down and two more after you have stood for 30 minutes (or for as long as you are able) to
determine levels of hormones that regulate blood pressure.  We will also monitor your blood pressure and
heart rate during this study.  Your blood pressure and heart rate will be monitored while you are lying down,
immediately after standing, and at 3, 5, 10, 20, and 30 minutes of standing. The length of time that you are
able to stand will be determined.  You will be asked about your symptoms periodically during the study.  You
will undergo a Posture Study before any medication is given.
g.
Orthostatic vital signs
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
Revision Date:  12/11/17
Study Title:  The Treatment of Orthostatic Hypotension  
Institution/Hospital: Vanderbilt University 
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Orthostatic vital signs will be measured several times a day while you are an inpatient.  This testing consists of 
blood pressure and heart rate measured while you are lying down and then repeated after standing quietly for 
10 minutes.  Several readings are measured in sequence using the Dinamap, an automated blood pressure 
monitor that uses a cuff around your upper arm. 
h.
Blood sampling
It will be necessary to collect two samples of your blood during each Posture Study (a total of 4 tablespoons
per study) for measurement of the hormones that control blood pressure.  To avoid sticking you repeatedly,
we will place a small plastic tube (catheter) in your arm vein.
 Our goal is to find a dosage that results in a standing blood pressure of at least 100/70 mm Hg. 
The drug that 
you will take is checked below: 

L-DOPS, starting at 25 mg with increments as tolerated (for example, 50 mg, 100 mg, 200 mg, 300 mg…)
given up to 4 times daily.

L-Dopa, starting at 25 mg with increments as tolerated (for example, 50 mg, 100 mg, 150 mg, 200 mg, 250
mg), given three times daily.

Carbidopa, starting at 25 mg with increments as tolerated to 25 mg four times daily.

Metyrosine, starting at 62.5 mg with increments as tolerated (for example, 125 mg, 250 mg, 500 mg, 750
mg, 1000

mg), given three times daily.

Metoclopramide (Reglan), starting at 10 mg up to four times a day as tolerated.

Alpha-methyldopa (Aldomet), starting at 62.5 mg with increments as tolerated to 250 mg given two times
daily.

Atomoxetine, starting at 10 mg with increments as tolerated to 20 mg and then 40 mg, given two times daily.

Placebo
If you are given a trial with an additional drug, you will be asked to sign an additional consent form with that drug
indicated.
3.
Costs to you if you take part in this study:
If you agree to take part in this research study, you and/or your insurance will not have to pay for the tests and
treatments that are being done only for research. However, you are still responsible for paying for the care
you receive that is being done as part of treating your illness or condition and other health care. This
includes treatments and tests you would need whether you are in this study or not. These costs will be billed to
you and/or your insurance.
4.
Side effects and risks that you can expect if you take part in this study:
Stopping medications might worsen your symptoms of lightheadedness, palpitations, fatigue and others that 
accompany your condition.  We will not ask you to stop any medication that will endanger your health and will 
admit you to the hospital if there is concern about your symptoms becoming too severe.  We will communicate 
with you on a daily basis after stopping medications.  While you are an inpatient on the CRC, we will check your 
general condition, blood pressure and heart rate regularly to reduce any risk. 
Consuming a sodium- and caffeine-controlled diet that needs to be picked up at the CRC might be 
inconvenient.  The low salt diet might be bland and not to your liking.  If you drink caffeinated beverages regularly 
Date of IRB Approval: 11/21/2019
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Date of Expiration: 11/20/2020


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
Revision Date:  
12/11/17
Study Title:  The Treatment of Orthostatic Hypotension 
Institution/Hospital: Vanderbilt University 
4 of 7
and you stop caffeine intake suddenly, you might have headaches and fatigue for a few days.  You can avoid these 
symptoms if you cut down gradually on the amount of caffeine in your diet. 
Staying in the hospital might be an inconvenience for you. 
Frequent blood pressure measurements with the cuff around your arm or finger may produce some discomfort and 
occasional bruising of the upper arm. 
There are minor risks and discomforts associated with blood sampling.  We will insert a plastic catheter into the vein to 
allow drawing blood without repeated sticks during the study.  This may cause a brief period of pain and possibly a small 
bruise at the site.  Occasionally, a person feels faint when their blood is drawn.  Rarely, an infection develops which can be 
treated.  There is a small risk of bleeding after removal of the catheter and possibly a bruise at the site which can be 
prevented by tight compression on the site.  Rarely, an infection develops which can be treated. As part of being in this 
study, you will have several blood draws that may worsen your anemia.  Symptoms may include feeling faint, low blood 
pressure, and fatigue.  This may require an increase in the length of time you are in this study, which may include 
additional visits to the CRC.  
Collecting your urine might be inconvenient for you.  We try to make it more convenient by fitting the toilet with a 
collection device and/or providing a urinal for your use. 
When any medication is used in testing, there is a small risk of an unforeseeable life-threatening allergic reaction.  Side 
effects associated with specific medications are listed below.  Side effects are listed as common, uncommon, and rare.  
-Methyldopa – common: weakness, distention of lower abdomen, constipation, swelling of the lower extremities, 
fever and depression, anxiety, nightmares, being sleepy or drowsy, headache and dry mouth.  Uncommon:  
dizziness, gas, diarrhea, chest pain, stuffiness of the nose, low blood pressure on standing, low heart rate, nausea 
or vomiting, abnormal liver function tests.  Serious or life-threatening: extremely rare reactions are fatal liver 
damage and fatal inflammation to the heart. 
Carbidopa – only reported to have adverse effects when it is given with the drug levodopa for Parkinson’s 
disease.  Common adverse events with the carbidopa-levodopa combination include dyskinesias (involuntary 
muscle movements) and nausea.  Less common adverse effects are psychotic episodes, depression and 
dementia (confusion/memory loss). 
Metyrosine – common: elevated blood pressure and heart rate, drowsiness, diarrhea, drooling, trembling and 
shaking of hands and fingers; trouble speaking. Uncommon: decreased sexual ability in men, dry mouth, nausea, 
vomiting, stuffy nose, anxiety, confusion, hallucinations, mental depression. Rare or life-threatening: crystalluria 
(the excretion of crystals in the urine resulting in urine retention),  black, tarry stools, unusual bleeding or bruising, 
muscle spasms, painful urination, pinpoint red spots on skin, restlessness, shortness of breath, shuffling walk, 
skin rash and itching, swelling of feet or lower legs, tic-like movements 
L-Dopa (levodopa) – common: abdominal pain, dry mouth, loss of appetite, nightmares, gas, abnormal thoughts,
feeling overly excited/sensitive, anxiety, clumsiness, difficulty swallowing, dizziness, excessive watering of mouth,
nausea and vomiting, uncontrolled body movements.  Uncommon: Chest pain, mood or mental changes,
discoloration of sweat or urine, constipation, diarrhea, flushed skin, headache, hiccups, increased sweating,
muscle twitching, trouble sleeping, blurred vision, difficult urination, dilated pupils, dizziness or lightheadedness
when getting up from a lying or sitting position, double vision, fast or pounding heartbeat, hot flushes, mental
depression, skin rash, weight gain or loss. Rare: back or leg pain, black tarry stools, chills, convulsions, fever, high
blood pressure, loss of appetite, swelling of feet or lower legs
Date of IRB Approval: 11/21/2019
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Date of Expiration: 11/20/2020


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
 
Revision Date:  
12/11/17
Study Title:  The Treatment of Orthostatic Hypotension  
Institution/Hospital: Vanderbilt University 
5 of 7
Atomoxetine – common: headache, nausea, sleepiness, trouble sleeping, anxiety, dry mouth, loss of appetite, 
dizziness, constipation, flushed or warm sensation, rash. Uncommon: loose stools, excessive energy, excitement, 
stomach ache, fluttering sensation in chest, abnormal heart rhythm sensations, tingling, vomiting, aching muscles. 
Rare: abnormal blood tests, such as abnormal liver function tests 
L-DOPS – The use of L-DOPS is under investigation and is not approved by the FDA.  We have used it for many 
years in a small population of patients that lack dopamine-beta-hydroxylase, the enzyme that converts dopamine 
to norepinephrine.  The initial dose is low and adjusted to treat low blood pressure without adverse effects.  It is 
possible that there may be some side effects.  The following rare side effects have been reported: increased blood 
pressure, nausea, headache, hallucination, anorexia, increased liver enzymes, dizziness/lightheadedness, heart 
fluttering, thirst, nervousness, stomachache, vomiting, abdominal pain, chest pain, and fatigue. 
Metoclopramide – common: diarrhea, drowsiness, restlessness, insomnia, fast heart rate, confusion.  
Uncommon: chills, increase in blood pressure, dizziness, headache, nausea, rash.  Rare: seizures, abnormal body 
movements, abnormal blood count, breast tenderness, increased flow of breast milk. 
Placebo – The placebo is a pill or capsule that does not contain active ingredient.  It should therefore have no side 
effects. 
5. Risks that are not known: 
We cannot foresee any other risks, but there may be previously unknown or unforeseen risks. Because the medications 
might be harmful to an unborn child, adequate birth control measures (i.e., oral, implanted or barrier methods) must be 
used by all participants and their sexual partners while participants are enrolled in this study.  If you become pregnant or 
father a child while in this study, you must notify your physician immediately.  In addition, women must not breast feed 
while in this study.  To rule out pregnancy prior to receiving treatment in this study, women of childbearing potential will 
have a pregnancy test. 
  
6.
Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the tests or treatments that 
are done for research, then you and/or your insurance will not have to pay for the cost of immediate medical care provided 
at Vanderbilt to treat the injury.  
There are no plans for Vanderbilt to pay for the costs of any additional care. There are no plans for Vanderbilt to give you 
money for the injury.  
7. Good effects that might result from this study:  
The potential benefits to science and humankind that may result from this study are that we might learn more about 
what causes disorders such as yours and possibly about treatments that might be effective for these disorders. 
8.  
Other treatments you could get if you decide not to be in this study: 
You may choose not to participate in this study. Along with your other doctors, we will still care for you even if you choose 
not to participate in this study.  
9. Payments for your time spent taking part in this study or expenses: 
You will not be compensated for your participation in this study. 
10. Reasons why the study doctor may take you out of this study:   
The investigators or Vanderbilt may stop you from taking part in this study at any time if it is in your best interest, if you do 
not follow the study rules, or if the study is stopped.
Date of IRB Approval: 11/21/2019
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Date of Expiration: 11/20/2020


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
 
Revision Date:  
12/11/17
Study Title:  The Treatment of Orthostatic Hypotension  
Institution/Hospital: Vanderbilt University 
6 of 7
11. What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor.  Deciding to not be part of the study will not 
change your regular medical care in any way. 
12. Who to call for any questions or in case you are injured:  
If you should have any questions about this research study or possibly injury, please feel free to contact 
, David Robertson, M.D. 
, or Emily Garland, PhD, 
.
For additional information about giving consent or your rights as a participant in this study, please feel free to contact the 
Vanderbilt University Institutional Review Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
13. Confidentiality 
Much of the data will be entered into the password-protected Autonomic Dysfunction Center Database.  Hard copies of 
research results are maintained by the Autonomic Dysfunction Center research nurses in a locked room.  Data will be 
accessible to Dr. Robertson, other members of his research group, and his collaborators.  All data and research 
specimens will be maintained for an indeterminate period of time. All the investigators have completed Vanderbilt training 
in compliance with the HIPAA regulations.  Every effort will be made to protect and respect patient confidentiality and 
privacy within the limits of HIPAA.  
14. Authorization to Use/Disclose Protected Health Information
Protected health information (PHI) is individually identifiable health information that has been entered into a medical 
record. Once this has occurred, use or disclosure of such information from the medical record must follow federal privacy 
guidelines. A decision to participate in this research means that you agree to let the research team use and share your PHI 
as described below. 
  
As part of the study, Dr. Robertson and his co-investigators may report the results of your study and/or non-study related 
laboratory tests and electrocardiograms to other members of his research team and to his collaborators. If your research 
record is reviewed by any of these groups, they may also need to review your entire medical record. Your records may also 
be reviewed in order to meet federal or state regulations.  Reviewers may include representatives from the Food and Drug 
Administration, representatives of the National Institutes of Health, the Vanderbilt University Institutional Review Board, or 
the research group headed by 
. Once your health information is released to the persons or 
groups described above, there is no guarantee that those persons or groups will not in turn release your health information 
to others who may not be legally required to follow the procedures and limitations in this Informed Consent and 
Authorization Form. 
The study results will be retained in your research record for at least six years after the study is completed.  At that time 
the research information not already in your medical record will be kept indefinitely. Any research information in your 
medical record will be kept indefinitely. 
If you decide to withdraw your authorization to use or disclose your PHI, we ask that you contact Dr. Robertson in writing 
and let him know that you are withdrawing your authorization.  His mailing address is: 
Dr. David Robertson 
Date of IRB Approval: 11/21/2019
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Date of Expiration: 11/20/2020


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Emily M. Garland, PhD, MSCI 
 
Revision Date:  
12/11/17
Study Title:  The Treatment of Orthostatic Hypotension  
Institution/Hospital: Vanderbilt University 
7 of 7
At that time we will stop getting any more data about you.  But, the health data we stored before you withdrew your 
consent may still be used for reporting and research quality.  
You have the right to see and copy the PHI we gather on you for as long as the study doctor or research site holds this 
data.  To ensure the scientific quality of the research study, you will not be able to review some of your research 
data until after the research study is finished. 
If you decide not to take part in this research study, it will not affect your treatment, payment or enrollment in any 
health plans or affect your ability to get benefits. You will get a copy of this form after it is signed.  
STATEMENT BY PERSON AGREEING TO PARTICIPATE IN THIS STUDY 
[  ] 
I have read this consent form.  All my questions have been answered, and I freely and voluntarily 
choose to participate.  I understand that I may withdraw at any time. 
[   ] 
I have read this informed consent document and the material contained in it has been explained to 
me verbally.  All my questions have been answered, and I freely and voluntarily choose to 
participate.   
_____  
 
 
 
 
 
_____________ 
Date 
 
 
 
Signature of patient/volunteer 
 
 
 
 
Consent obtained by: 
 
__________________  
_____________________________________________  
 
 
Date 
 
 
 
Signature 
 
 
 
_____________________________________________
 
 
 
 
Printed Name and Title 
Date of IRB Approval: 11/21/2019
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Date of Expiration: 11/20/2020