Conditions: Postural Tachycardia Syndrome Orthostatic Intolerance
Keywords: Dopamine Natriuresis Catecholamines
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 32
Healthy volunteers: yes

Brief summary:
The purpose of the proposed research is to determine how changes in kidney dopamine (DA) activity influence urinary sodium excretion. We will decrease DA activity in the kidney by inhibiting DA synthesis via carbidopa administration. We want to compare findings in normal volunteers and in patients with postural tachycardia syndrome (POTS). We will test the null hypothesis (Ho) that the effects of oral carbidopa administration on urinary sodium excretion will not differ between patients with POTS and healthy volunteers.

Detailed description:
We will determine whether inhibition of renal dopamine formation by carbidopa administration leads to a decrease in urinary excretion of dopamine and sodium and whether the response differs in POTS and control populations. Carbidopa effects will be compared to those of a matching placebo, and the sequence of treatments (carbidopa before placebo or placebo before carbidopa) will be randomized.

Each subject will undergo a complete history and physical examination, including an electrocardiogram (EKG).

* After achieving sodium balance on a 200 mEq/day sodium diet, subjects will collect urine over 24hr for baseline assessment of sodium and catecholamines.
* On this day, the subjects will be admitted to the CRC.
* An 18 gauge intravenous catheter will be inserted in order to draw blood.
* The subjects will fast from 7 pm until after the next morning's testing.
* In the morning, while still supine after the overnight sleep, heart rate and blood pressure will be recorded, and blood will be drawn. The subjects will then stand for 10 minutes. Heart rate and blood pressure will be measured at intervals, and an upright blood sample will be collected.
* The subjects will be asked to collect their urine to end the 24hr urine collection. Another 24hr urine collection will be started.
* Treatment A (Carbidopa 200mg or placebo) will be given orally following the void, at approximately 7 am. Additional doses will be taken every 6 hours with the last dose at 7 am the following morning.
* Subjects will be free to follow their normal routine during the day until returning to the CRC for the night. However, they will need to consume the 200 mEq/day study diet for each meal, collect all urine, and take study medication on schedule
* After returning to the CRC, the subjects will fast after 7 pm.
* In the morning, supine and standing heart rate and blood pressure will be recorded, and the subjects will be asked to collect their urine to end the 24hr urine collection.
* The final dose of study medication (Carbidopa 200mg or placebo) will be given orally following the void, at approximately 7 am.
* Supine heart rate and blood pressure will be measured and supine blood samples will be collected hourly for 4 hours after the treatment and at 8 hours after the treatment. Subjects must rest supine for at least 30 minutes before each blood draw.
* At 2 hours after treatment, subjects will stand for 10 minutes for upright blood pressure and heart rate measurements and collection of an upright blood sample, as described above. Participants will be asked to rate the severity of common orthostatic symptoms while supine and upright.
* Urine will be collected for two 4-hour periods after treatment and from 8 hours to 24 hours after treatment.
* Fixed-sodium study diet will be provided after the 4-hour measurements and in the evening.

After at least a 1 day washout period, the study will be repeated with Treatment B

Arms:
arm 1: Carbidopa 200 mg every 6 hours orally for 5 doses followed by Placebo every 6 hours for 5 doses arm 2: Placebo matching carbidopa given every 6 hours orally for 5 doses followed by Carbidopa

Interventions: intervention 1: Carbidopa intervention 2: Placebo
Intervention descriptions: intervention 1: 200 mg every 6 hours for 5 doses given orally intervention 2: every 6 hours for 5 doses, given orally, and matching Carbidopa

Protocol document:
Prot_SAP_ICF_000.pdf: 
Protocol Title:  Peripheral Dopamine in Postural Tachycardia Syndrome
Protocol Date: 25 March 2013
NCT00685919


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
1
Rare Diseases Clinical Research Network 
Peripheral Dopamine after Carbidopa Administration in Postural 
Tachycardia Syndrome
Autonomic Rare Diseases Clinical Research Consortium
Study Chair   
Co-Investigator
Emily Garland, PhD, MSCI   
David Robertson, MD
Vanderbilt University Medical Center 
Vanderbilt University Medical Center
Clinical Pharmacology    
Clinical Pharmacology
   
Nashville, TN  
   
Nashville, TN  
Emily.garland@vanderbilt.edu
This protocol is for research purposes only and should not be copied, 
redistributed, or used for any other purpose.  The procedures in this protocol 
are intended only for use by the Autonomic Rare Diseases Clinical Research 
Consortium investigators in carefully controlled settings.  The Study Chair of 
this study should be consulted before using this protocol.
oses only a
other purpo
y the Auton
in carefully
onsulted be
ratio
atio
esearch
esearc


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
2
Participating Institutions Table
INSTIUTION, SITE PRINCIPAL INVESTIGATOR
Contact: 
Emily Garland, PhD, MSCI
Institution:
Vanderbilt University Medical Center, Clinical Pharmacology
Address:
Phone:
Fax:
Email:
Emily.garland@vanderbilt.edu
INSTIUTION, SITE PRINCIPAL INVESTIGATOR
Contact: 
David Robertson, MD
Institution:
Vanderbilt University Medical Center, Clinical Pharmacology
Address:
Phone:
Fax:
Email:
Data Management and Coordinating Center, Principal Investigator: Jeffrey Krischer, Ph.D.
Contact: 
 Research Project Manager
Institution/ 
Department:
Data Management and Coordinating Center (DMCC); Pediatrics Epidemiology 
Address:
Phone:
Fax:
Email:
stigator: J
stigator: J
ter (DM
er (D
CC
CC


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
3
Table of Contents 
1. Synopsis.............................................................................................................................................................................. 4
2. Objectives and Research Question .................................................................................................................................... 6 
3.  Background........................................................................................................................................................................ 9 
4.  Study Design and Methods.............................................................................................................................................. 12
4.A Inclusion criteria ....................................................................................................................................................... 12
4.B Exclusion Criteria ..................................................................................................................................................... 13
4.C Recruitment of Participants...................................................................................................................................... 13
4.D Retention Strategies ................................................................................................................................................ 13
4.E Data Elements ......................................................................................................................................................... 14
4.F Schedule of Events .................................................................................................................................................. 18
Table 1.  Study Day Description (Carbidopa and Placebo).............................................. Error! Bookmark not defined.
5.  Data and Safety Monitoring Plan ..................................................................................................................................... 19 
6.  Statistical Considerations................................................................................................................................................. 23
7. Data Management ............................................................................................................................................................ 23 
7.A Registration.............................................................................................................................................................. 24
7.B Data Entry ................................................................................................................................................................ 24
7.C Laboratory data flow ................................................................................................................................................ 24
8.  Human Participants.......................................................................................................................................................... 24 
8.A Human participants involvement and characteristics............................................................................................... 25
8.B Informed consent ..................................................................................................................................................... 25
8.C Potential risks........................................................................................................................................................... 25
8.D Protection against risk ............................................................................................................................................. 26
8.E Potential benefits of the proposed research to the participants and others ............................................................ 26
8.F Importance of the knowledge to be gained .............................................................................................................. 26
8.G Confidentiality .......................................................................................................................................................... 26
8.H Financial considerations .......................................................................................................................................... 27
8.I Conflict of interest...................................................................................................................................................... 27
9.  References....................................................................................................................................................................... 28 
10. Appendices ..................................................................................................................................................................... 22
APPENDIX 1a: Sample Informed Consent Form- POTS ..................................................................................................... 30
APPENDIX 1b: Sample Informed Consent Form – Healthy Volunteer ................................................................................ 36
APPENDIX 1c:  Sample Informed Consent - Dose Escalation - POTS………………………………………………………….42
APPENDIX 1d: Sample Informed Consent - Dose Escalation - Health Volunteer……………………………………48 
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.


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
4
1. Synopsis
Protocol Number:
ARD6101
Protocol Title:
Peripheral Dopamine after Carbidopa Administration in Postural Tachycardia 
Syndrome
Study Chair:
Emily Garland, PhD and David Robertson, MD
Statistician:
Consortium:
Autonomic Rare Diseases Clinical Research Consortium
Participating Sites:
Vanderbilt University Medical Center
Activated by Vanderbilt, Date:
May 2008
Activated by RDCRN, Date:
April 2011
Sample Size:
16/group (32 total for participants with POTS and healthy controls)
To allow for participant drop-out prior to study completion, we will plan to obtain 
informed consent from 35 participants in total (18 POTS, 17 Controls). 
Target Enrollment Period:
5 yr
Study Design:
Randomized, double-blind, placebo-controlled crossover
Primary Study Objective:
The purpose of the proposed research is to determine how changes in kidney 
dopamine (DA) activity influence urinary sodium excretion.  Dopamine in the 
kidney plays an important role in maintaining sodium balance.  We will decrease 
DA activity in the kidney by inhibiting DA synthesis via carbidopa administration.  
We will compare urinary sodium excretion following the active agent and a placebo
in participants with POTS and healthy controls. Urinary and plasma 
catecholamines will be measured to assess changes produced by carbidopa 
treatment. A dose escalation study with doses of 50mg, 100mg and 200mg will 
first be conducted to assess how well these doses are tolerated when given every 
6 hours.
Secondary Study Objective:
We also want to compare findings in normal volunteers and in participants with 
postural tachycardia syndrome (POTS). These patients are characterized by an 
excessive increase in heart rate with standing. To determine whether some of 
these patients do not effectively regulate sodium excretion, the catecholamine, 
diuretic, and cardiovascular responses following orally administered carbidopa in 
participants with POTS will be compared with those of healthy volunteers. The 
dose escalation study will therefore include both POTS and controls.
Study Population and Main 
Eligibility/ Exclusion Criteria:
Inclusion Criteria:
Healthy volunteers,free from symptoms of orthostatic intolerance and 
without any chronic medical condition
o
Non-smoking
o
Free of medications with the potential to influence blood pressure 
(BP)
o
Age between 18-60 years
o
Male and female participants are eligible
o
Able and willing to provide informed consent
Patients diagnosed with POTS by the Vanderbilt Autonomic Dysfunction 
Center based on the following stringent criteria: 1) history of daily 
orthostatic symptoms for at least 6 months; 2) increase in heart rate (HR) 
of at least 30 bpm with standing or a standing HR
120 bpm; 3) absence 
of orthostatic hypotension (defined as a fall in BP>20/10 mm Hg); and 4) 
absence of conditions, such as dehydration, substantial weight loss, or 
systemic illnesses, that could provoke orthostatic intolerance
o
Non-smoking
o
Free of medications with the potential to influence BP  
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
5
o
Age between 18-60 years
o
Male and female participants are eligible
o
Able and willing to provide informed consent
Exclusion Criteria:
Overt cause for postural tachycardia (such as acute dehydration)
Significant cardiovascular, pulmonary, hepatic, or hematological disease 
by history or screening results
Positive urine b-hcg pregnancy test or breastfeeding
Evidence of cardiac structural disease (by clinical examination or prior 
echocardiogram)
Hypertension defined as a BP>145/95 (off medications) or need for 
antihypertensive medications
Evidence of significant conduction system delay (QRS duration >120 ms) 
on electrocardiogram
Known allergy to FD&C Yellow dye 6
Inability to give, or withdraw, informed consent 
Other factors which in the investigator’s opinion would prevent the 
participant from completing the protocol, including poor compliance during 
previous autonomic studies or an unpredictable schedule
Participants in the dose escalation part of the study are excluded from 
participation in the main study.
Primary Outcome Measures:
For the dose escalation study, results from the labs, ECG, Psychiatric 
Questionnaire and vital signs will be evaluated. For the main study, the primary 
outcome is the urinary sodium concentration normalized to creatinine.
Secondary Outcome 
Measures:
Plasma and urinary catecholamines
Blood pressure and heart rate
Plasma sodium
Plasma renin activity
Statistical Considerations 
(sample size and analysis 
plan):
Based on our preliminary findings of a standard deviation for urinary sodium 
excretion of 30 mEq/g creatinine, a sample size of 16/group (32 total) will have 
80% power to detect a difference in group means (control vs. POTS) of 31 mEq/g 
creatinine with a 0.05 two-sided significance level. To allow for participant drop-out 
prior to study completion, we will plan to obtain informed consent from 35 
participants in total.
Differences in urinary sodium in samples (1) collected at baseline vs. those 
collected following treatment (time effect) and (2) collected after placebo vs. 
carbidopa (treatment effect) will be assessed using a paired t-test and Wilcoxon 
signed-rank test.  Differences between the patient and control groups (group 
effect) will be assessed using a student’s t-test and a Mann-Whitney U test.  
Similar methods will be used to compare secondary outcome measures, such as 
BP, HR, plasma and urinary catecholamines, plasma renin activity, plasma 
aldosterone, and plasma sodium. All data analyses will be performed using SPSS 
14.0 (SPSS, Chicago, IL) or STATA 8.2 (StataCorp, College Station, TX).  All 
statistical tests will be two-sided. If these analyses indicate that the response to 
carbidopa differs between patients and controls, a mixed-effects model will be 
developed to describe the time, medication and group effects. 
Sponsors (federal, state, 
foundation and industry 
support):
National Institutes of Health (NIH)
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heart


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
6
1.A.  Protocol Overview
The purpose of the proposed research is to determine how changes in kidney dopamine (DA) activity influence 
urinary sodium excretion. Dopamine in the kidney plays an important role in maintaining sodium balance.  We will 
decrease DA activity in the kidney by inhibiting DA synthesis via carbidopa administration.  We will compare the 
active agent with a placebo.  We also want to compare findings in normal volunteers and in patients with postural 
tachycardia syndrome (POTS). Some of these patients may not effectively regulate sodium excretion.  
1.B. Dose Escalation Study of Carbidopa
Prior to initiation of the main study, a dose escalation study will be conducted. A cohort consisting of one 
healthy volunteer and one participant with POTS will be administered a dose of 50mg carbidopa every 6 hours for a 
total of five doses. If this dosage is well-tolerated (see next paragraph), a second cohort will be given five doses of 
carbidopa 100mg with 6 hours between doses. If this dosage is well-tolerated, a final cohort will take the proposed 
dose of 200mg carbidopa every 6 hours for five doses. All participants in the dose escalation study will also take 
placebo every 6 hours for five doses, according to a crossover design, and will undergo the same measurements 
and procedures as described below for the main study. However, additional blood draws and monitoring will be
included. 
Specific aims of Dose Escalation Study. 
1.
To assess tolerability of increasing doses (50mg, 100mg, 200mg) of carbidopa, as assessed by ECG, 
complete blood count (CBC), chemistry panel, liver function biomarkers, and a Psychiatric Symptom 
Questionnaire.
2.
To assess plasma carbidopa levels after different doses of carbidopa.
3.
To obtain preliminary data on the changes in plasma and urinary levels of catecholamines and urinary 
sodium excretion following oral administration of different doses of carbidopa.
4.
To obtain preliminary data on the effect of oral administration of different doses of carbidopa on orthostatic 
changes in heart rate and blood pressure, as well as symptoms.
5.
To compare the tolerability, as well as catecholamine, diuretic, and cardiovascular responses following 
orally administered carbidopa in participants with POTS with those of healthy volunteers.
To accomplish these aims:
Pre-study assessments consist of 1) 12-lead ECG; 2) complete blood count (CBC) with 
platelets; 3) chemistry panel including albumin, total bilirubin, alkaline phosphatase, serum 
glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase
(SGPT) to evaluate liver function; and 4) plasma carbidopa.
Participants will be provided a 200 mEq/day sodium diet, free of methylxanthines and low 
in monoamines, by the kitchen of the Clinical Research Center (CRC).
After achieving sodium balance on the study diet over 2-3 days, participants will collect 
urine over 24hr for baseline assessment of sodium and catecholamines and to confirm 
adherence to the study diet. 
On this day, the participants will be admitted to the CRC. 
An 18 gauge intravenous catheter will be inserted in order to draw blood. 
The participants will fast from 7 pm until after the next morning's testing. 
In the morning, while still supine after the overnight sleep, heart rate (HR) and blood 
pressure (BP) will be recorded, and blood will be drawn. The participants will then stand for 
10 minutes. HR and BP will be measured at intervals, and an upright blood sample will be 
collected. 
The participants will be asked to collect their urine at the end of the 24hr urine collection. 
Another 24hr urine collection will then be started. 
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
7
Treatment A (carbidopa or placebo) will be given orally following the void, at approximately 
7 am. Additional doses will be taken every 6 hours with the last dose at 7 am the following
morning. 
Participants will remain inpatients on the CRC during the day. They will need to consume 
the 200 mEq sodium/day study diet for each meal, collect all urine, and take study 
medication on schedule. Supine BP and HR will be measured and blood will be collected 
for plasma carbidopa 2hr after each dose.
 
The participants will fast after midnight except for water and medication.
In the morning, supine and standing HR and BP will be recorded, and the participants will 
be asked to collect their urine to end the 24hr urine collection. 
The final dose of study medication (carbidopa or placebo) will be given orally following the 
void, at approximately 7 am. 
Supine HR and BP will be measured and supine blood samples will be collected hourly for 
4 hours after the last dose and at 8 hours after the dose. Participants must rest supine for 
at least 30 minutes before each blood draw. Plasma carbidopa will be measured at 2hr, 4hr 
and 8hr after the 5th dose. The intravenous catheter will be removed following the 8-hour 
blood draw.
At 2 hours after the 5th dose, participants will stand for 10 minutes for upright BP and HR 
measurements and collection of an upright blood sample, as described above. Participants
will be asked to rate the severity of common orthostatic symptoms while supine and 
upright. 
As part of the safety assessment, the 12-lead ECG, CBC and chemistry panel will be 
repeated 2hr after the fifth dose.
Urine will be collected for two 4-hour periods after the 5th dose followed by a 16-hour 
collection to finish the 24-hour cycle
Participants may be discharged approximately 8 hours after the last dose or, if they prefer, 
they may remain on the CRC for the washout day.
After at least a 1 day washout period, the study will be repeated with Treatment B.
Treatment B consists of exactly the same regimen as Treatment A.  The participant will be 
randomized to receive placebo or carbidopa (whichever was not given during Treatment 
A).
Throughout the dosing period, participants will be monitored (HR and BP measurement, Psychiatric Symptom 
Questionnaire, and questioning by study personnel 2hr after each dose) for adverse events, including allergic 
reaction, nausea, worsening hypotension or tachycardia, arrhythmia, neuroleptic malignant syndrome, 
hallucinations or other psychiatric symptoms. No more doses will be given to a participant who experiences an 
allergic reaction, arrhythmia, increased body temperature >100.4°F, or >38°C, changes in supine BP>20mmHg or 
changes in supine HR>30bpm, hallucinations or psychiatric symptoms (as determined by our Psychiatric Symptom 
Questionnaire).  Adverse events and post-study changes in ECG or laboratory values (in relation to pre-study 
assessments) following carbidopa and placebo will be summarized for each cohort. Adverse events will be defined 
according to the Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE). 
, the Independent Medical Monitor (IMM) for this study, will review the data and use clinical 
judgment to decide whether to proceed to the next higher dosage of the dose escalation study.  In general, a grade 
2 event in more than one participant or a grade 3 event judged to be drug-related in any one participant will lead to 
study termination. Post-dose laboratory assessments may be repeated to confirm abnormalities.
Participants in the dose escalation study will not be allowed to also participate in the main study.
1.C. Detailed Description of Main Study:  
This study will only be conducted if the results of the dose escalation study indicate that the 200mg dosage of 
carbidopa is well tolerated when given every 6hr for 5 doses. We will determine whether inhibition of renal 
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
8
dopamine formation by carbidopa administration leads to a decrease in urinary excretion of dopamine and sodium 
and whether the response differs in POTS and control populations. Carbidopa effects will be compared to those of 
a matching placebo, and the sequence of treatments (carbidopa before placebo or placebo before carbidopa) will 
be randomized.
Each participant will undergo a complete history and physical examination, including an electrocardiogram (EKG).
Participants will be provided a 200 mEq/day sodium diet, free of methylxanthines and low 
in monoamines, by the kitchen of the Clinical Research Center (CRC).
After achieving sodium balance on the study diet over 2-3 days, participants will collect 
urine over 24hr for baseline assessment of sodium and catecholamines and to confirm 
adherence to the study diet. 
On this day, the participants will be admitted to the CRC. 
An 18 gauge intravenous catheter will be inserted in order to draw blood. 
The participants will fast from 7 pm until after the next morning's testing. 
In the morning, while still supine after the overnight sleep, heart rate and blood pressure 
will be recorded, and blood will be drawn. The participants will then stand for 10 minutes. 
Heart rate and blood pressure will be measured at intervals, and an upright blood sample 
will be collected. 
The participants will be asked to collect their urine to end the 24hr urine collection. Another  
urine collection will be started. This may take the form of one 24 hr sample or two 4 hr 
collection samples followed by a 16 hr sample collected from approximately 3 pm to 7am 
the following morning. The second schedule will facilitate comparison to urinary excretion 
after the final dose.
Treatment A (Carbidopa 200mg or placebo) will be given orally following the void, at 
approximately 7 am. Additional doses will be taken every 6 hours with the last dose at 7 
am the following morning. 
Participants will remain inpatients on the CRC during the day. They will need to consume 
the 200 mEq sodium/day study diet for each meal, collect all urine, and take study 
medication on schedule. Supine BP and HR will be measured 2hr after each dose.
The participants will fast after midnight except for water and medication.
In the morning, supine and standing heart rate and blood pressure will be recorded, and 
the participants will be asked to collect their urine to end the 24hr urine collection. 
The final dose of study medication (Carbidopa 200mg or placebo) will be given orally 
following the void, at approximately 7 am. 
Supine heart rate and blood pressure will be measured and supine blood samples will be 
collected hourly for 4 hours after the last dose and at 8 hours after the treatment. 
Participants must rest supine for at least 30 minutes before each blood draw. The 
intravenous catheter will be removed following the 8-hour blood draw.
At 2 hours after the 5th dose, participants will stand for 10 minutes for upright blood 
pressure and heart rate measurements and collection of an upright blood sample, as 
described above. Participants will be asked to rate the severity of common orthostatic 
symptoms while supine and upright. 
Urine will be collected for two 4-hour periods after the last dose followed by a 16-hour 
collection to finish the 24-hour cycle. 
Participants may be discharged approximately 8 hours after the last dose or, if they prefer, 
they may remain on the CRC for the washout day(s).
Fixed-sodium and low monoamine and methylxanthine-free study diet will be provided after 
the 4-hour measurements and in the evening. 
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
9
Figur
Figure 1.
After at least a 1 day washout period, the study will be repeated with Treatment B
2.  Objective and Research Question of the Main Study
Specific aims.
1.
To assess normal changes in plasma and urinary levels of catecholamines following oral carbidopa 
administration. 
We are giving 200mg of carbidopa every 6 hours for 5 doses. We expect that this treatment will 
decrease the formation of dopamine in the kidney so that urinary dopamine will be lowered and its 
precursor, urinary dopa, will be raised.
2.
To assess the relationship between catecholamines and urinary sodium excretion following oral carbidopa 
administration. 
Because of the important role of kidney dopamine in regulating urinary sodium excretion, we expect 
that urinary sodium excretion will be decreased as urinary dopamine falls.
3.
To assess the effect of oral carbidopa administration on orthostatic changes in heart rate and blood 
pressure, as well as symptoms.
Because of the relationship between sodium excretion and blood pressure control, we expect that a 
carbidopa-mediated decrease in urinary sodium excretion may be associated with an increase in blood 
pressure.
4.
To compare the catecholamine, diuretic, and cardiovascular responses following orally administered 
carbidopa in participants with POTS with those of healthy volunteers.
One of the most consistent findings in POTS is a reduction in plasma volume or blood volume.
Previous findings by our research group suggest that mechanisms involved in orthostatic and absolute 
volume regulation contribute to POTS pathophysiology. We have preliminary data showing that 
patients with POTS do not decrease urinary sodium excretion after 30-60 minutes of upright posture,
whereas healthy control participants do.  We also reported that plasma renin activity (PRA) and 
aldosterone are paradoxically low in POTS in view of the reduced plasma volume. This indicates that 
sodium handling is perturbed in POTS. We therefore expect that patients with POTS may benefit from 
a reduction in urinary sodium excretion or that carbidopa-mediated changes in sodium excretion may 
differ between patients with POTS and healthy volunteers.  
Hypothesis: In these studies, we will test the null hypothesis (Ho) that the effect of oral carbidopa 
administration on urinary sodium excretion will not differ between participants with POTS and healthy 
volunteers.  
Research Question:  Does orally administered carbidopa, by blocking the formation of renal dopamine from 
dopa, decrease urinary dopamine and sodium excretion in POTS and normal participants? 
3.  Background
Synthesis and degradation of catecholamines. The synthesis of catecholamines is summarized in Figure 1.  
Tyrosine hydroxylase (TH) is the rate-limiting step in norepinephrine (NE) synthesis under almost all circumstances. 
NE acts as a feedback inhibitor of this enzyme. L-dopa (dopa) is the amino acid precursor of the endogenous 
catecholamines and the immediate product of TH.  L-Aromatic 
amino acid decarboxylase (AADC; also known as dopa 
decarboxylase or DDC) converts dopa to dopamine (DA) in both 
nonneural and neural tissues.  Dopamine-ß-hydroxylase (DBH), 
which converts DA to NE, is localized in vesicles of noradrenergic 
neurons in the central and peripheral nervous systems and in the 
adrenal medulla.  Phenylethanolamine-N-methyltransferase (PNMT; 
NE to epinephrine (EPI)) is restricted to the adrenal medulla, the 
brain, and the heart, with only trace amounts in other locations.  
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
10
The fate of released catecholamines includes a) uptake into the neuron by the norepinephrine transporter (NET; 
uptake I), b) uptake by the extraneuronal monoamine transporter (EMT; uptake II), or c) metabolic transformation. 
Intraneuronal NE is converted to dihydroxyphenylglycol (DHPG) by monoamine oxidase (MAO)[7].  Catechol-O-
methyltransferase (COMT) converts extraneuronal NE into normetanephrine (NMN), EPI into metanephrine (MN), 
and DA into 3-methoxytyramine (MT).  DA that is not transported into the DBH-containing vesicles is deaminated by 
MAO to 3,4-dihydroxyphenylacetic acid (DOPAC) which is subsequently O-methylated by COMT to homovanillic 
acid (HVA). The corresponding metabolite for NE is vanillylmandelic acid (VMA).
Functions of dopamine. In the brain, dopamine functions as a neurotransmitter, activating the five main types of 
dopamine receptor - D1, D2, D3, D4 and D5. Brain DA has been implicated in the control of movement and reward 
systems.  Dopamine, administered as a medication clinically, acts on the sympathetic nervous system to produce 
effects such as increased heart rate and blood pressure. Effects of DA are dose-related and dependent on the 
localization and characteristics of the receptors with which it interacts. At very low doses (1 to 2 ug/kg/min), it 
dilates renal and mesenteric blood vessels and increases renal blood flow, principally by actions on dopaminergic 
cardiac outpu
-adrenergic receptors 
and elevates arterial pressure. Since it cannot cross the blood-brain barrier, peripherally given dopamine does not 
directly affect the central nervous system. 
Dopamine as an autocrine/paracrine substance.  In addition to its role as a neurotransmitter and as a precursor 
to NE and EPI, non-neuronal DA also acts as a paracrine or autocrine substance, originating in the gastrointestinal 
tract and the kidney.  In the gut, DA is produced endogenously and is also derived from dietary sources.  DA 
undergoes sulfate conjugation in gastrointestinal tissues, and at least 95% of circulating DA occurs in the 
sulfoconjugated form. Ingestion of a standard meal or bananas raise plasma dopamine sulfate concentration more 
than 50-fold, whereas plasma dopa and DA increase much less[5;13].  Twelve hours of fasting have been shown to 
eliminate dopamine sulfate that comes from a dietary source[23]. Sulfoconjugation may contribute to a gut-blood 
barrier and limit the amount of ingested catecholamines that enter the bloodstream[13].  
Renal dopamine and sodium excretion.  In the kidney, DA is synthesized from circulating dopa in non-neuronal 
tissue and exerts local effects to facilitate natriuresis.  Renal DA is metabolized by COMT and MAO. The supply of 
dopa to the kidney is the primary regulatory factor for intrarenal non-neuronal DA synthesis[9]. Dopa is taken up 
into proximal tubule cells by a sodium-dependent process[27] and is rapidly converted to DA by the high 
concentrations of AADC found there.  Intrarenal DA induces natriuresis by inhibition of tubule sodium reabsorption 
via the Na+K+-ATPase pump and the Na-H exchanger. High salt intake in Caucasians produces a significant and 
sustained increase in urine DA output[12].  An increase in the filtered load of sodium promotes uptake of dopa by 
the proximal tubule cells[26;32], and AADC activity is also up-regulated by sodium[14]. Saline loading may also be 
associated with decreased renal degradation of DA by COMT[25] to 3MT and eventually to HVA. Carbidopa, by 
blocking the synthesis of DA from dopa, will prevent a rise in renal DA under high-sodium conditions. A low-salt 
diet, in contrast, decreases renal and urinary dopa and DA, without significantly changing plasma dopa[12].  DA 
exerts its renal actions through two families of receptors, designated D1-like and D2-like[20], which are identical in 
the brain and in peripheral tissues. The two D1-like receptors (D1 and D5) are linked to stimulation of adenylyl 
cyclase. D2, D3, and D4 are linked to inhibition of adenylyl cyclase. Inhibition by DA of the Na+K+-ATPase pump is 
thought to be mediated by D1 receptors.  D2 receptors may increase glomerular filtration rate and possibly 
contribute to natriuresis in the cortical collecting duct cells, but their role in the regulation of sodium excretion is not 
well understood[2]. 
The renin-angiotensin-aldosterone system interacts with the renal dopaminergic system to regulate plasma volume 
in humans. In response to DA, hypovolemia, a decrease in sodium, or an increase in renal sympathetic nerve 
activity, plasma renin activity is stimulated to produce angiotensin II.  Angiotensin stimulates sodium reabsorption 
directly and also stimulates the release and synthesis of aldosterone, a mineral corticoid hormone that causes the 
retention of sodium, increasing fluid volume. Further modulation of natriuresis is achieved by DA-mediated 
attenuation of aldosterone secretion[4]. 
Dopamine in cardiovascular regulation. This renal autocrine-paracrine function, which has heretofore been most 
evident during extracellular fluid volume expansion, is lost in essential hypertension[1] and in some animal models 
of genetic hypertension[3;18;21;24]. Animal models and genetic forms of hypertension demonstrate decreased 
al deg
de
from dop
from dop
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renal a
hrough tw
hrough tw
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tis
hat
ha
dney, DA is s
ey, DA is
sis.  Renal D
 Rena
ctor for intrare
r for in
ndent proces
ent pro
arenal DA in
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a-H exchang
H exch
ut
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.  An in
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so derive
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st 95% of 
aise plasm
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5;13].  T
.  T
e[23]
[23]. Sulfo
. Sulf
enter th
enter 


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
11
Figure 2. Plasma volume deficit in patients 
with POTS and healthy controls(2)
signal transduction by DA receptors in proximal tubule cells, and an impaired ability to increase urinary sodium 
excretion following a DA agonist[8], resulting in decreased sodium reabsorption[19]. This has been linked to an 
uncoupling of the D1 receptor from the G protein complex as a result of a GRK4 polymorphism[19]. 
Postural tachycardia syndrome. Postural tachycardia syndrome (POTS) is the most common form of orthostatic 
intolerance, affecting an estimated 500,000 Americans, principally young women. POTS refers to an excessive 
increase in heart rate (>30 beats per minute) on standing in the absence of orthostatic hypotension.  Patients 
typically experience symptoms of excessive sympathetic activation with physical or emotional exertion. POTS can 
produce substantial disability among otherwise healthy people.  The pathophysiology of POTS is heterogeneous 
and poorly understood.  Many of these patients have elevated levels of plasma NE, particularly when upright.  
Subgroups of patients have a primary hyperadrenergic state, while others suffer from a partial dysautonomia 
affecting the lower limbs.  
Plasma volume and its orthostatic shift in POTS. One of 
the most consistent findings in POTS is a reduction in plasma 
volume or blood volume (Figure 2)[10;11;17;29;31].
Furthermore, there are additional decrements in plasma 
volume due to orthostatic volume shifts[16;28].  The marked 
interindividual variation in the POTS group, with some patients 
having a volume shift that is well within the normal range, 
suggests that the POTS population is quite heterogeneous in 
terms of this variable.  
Previous findings by our research group suggest that 
mechanisms involved in orthostatic and absolute volume 
regulation contribute to POTS pathophysiology. We have 
preliminary data showing that patients with POTS do not 
decrease urinary sodium excretion after 30-60 minutes of 
upright posture, whereas healthy control participants do 
(Figure 3).  We also reported that PRA and aldosterone are 
paradoxically low in POTS in view of the reduced plasma volume. This indicates that sodium handling is perturbed 
in POTS.  Several investigators have implicated dopamine in the control of natriuresis in other disorders. 
Approximately 50% of sodium excretion appears to be under dopaminergic regulation. 
Uptake of dopa into the proximal tubule cells and its subsequent 
decarboxylation to DA are stimulated by a high salt diet. Carbidopa 
inhibits the activity of AADC in the periphery.  By blocking the 
conversion of dopa to DA, it has the potential to attenuate the effects 
of the sodium load on renal DA production and urinary sodium 
excretion.  However, since carbidopa also inhibits dopa 
decarboxylation in peripheral neurons, it can increase plasma dopa 
levels and the filtered load of dopa in the kidney.  The final effect of 
carbidopa on renal DA production is therefore the result of increased 
substrate and decreased decarboxylation[12].
Recommended dosages of carbidopa for the treatment of Parkinson’s
disease, as Sinemet
, are at least 70-100 mg, up to 200 mg daily 
(AHFS Drug Information 2007).  Yet, Durso et al.[6] speculated that 
“doses used in current practice” are not saturating for the 
decarboxylase enzyme. Kaufmann et al.[22] and Hershey et al.[15]
administered one dose of 200 mg carbidopa to ensure that the 
decarboxylase was completely inhibited. Stokes et al.[30] proposed that more than one dose of carbidopa must be 
given to see an effect on renal salt handling.  Based on this information and a carbidopa half-life of about 2 hours, 
we have chosen to administer 200 mg of carbidopa every 6hr.  We believe that with repeated dosing of 200 mg, we 
will be able to assess the influence of decarboxylase inhibition on urinary sodium excretion. Nevertheless, since 
this dosage is higher than that which is FDA approved, we will first conduct a dose escalation study with 50mg, 
100mg and 200mg of carbidopa to confirm that these dosages are well tolerate
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t


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
12
The following studies are designed to compare the influence of plasma dopa levels on plasma and urinary 
catecholamines in participants with POTS and healthy volunteers and to assess subsequent effects on sodium 
excretion.  We will evaluate the roles of peripheral dopa and DA in POTS by comparing the effects of placebo and 
carbidopa on urinary DA and sodium excretion in patients and controls. Study participants will consume a relatively 
high-salt diet to “turn on” the dopaminergic regulation of sodium excretion.  The dosage of carbidopa may be 
modified to attenuate or intensify the responses, not to exceed 1000mg in a 24hr period. 
4.  Study Design and Methods
We will determine whether inhibition of renal DA formation by carbidopa administration leads to a decrease in 
urinary excretion of DA and sodium and whether the response differs in POTS and control populations. Carbidopa 
effects will be compared to those of a matching placebo, and the sequence of treatments (carbidopa before 
placebo or placebo before carbidopa) will be randomized. The study is double-blinded.  The investigational 
pharmacy at Vanderbilt Medical Center determines the randomization and the treatment order. The same crossover 
design is used for both the dose escalation and main studies.   
Recruitment. The participants with POTS will be recruited for both dose escalation and main studies from patients 
referred to the Vanderbilt University Autonomic Dysfunction Center.  Control participants will be recruited from 
healthy volunteers known to the Autonomic Dysfunction Center, through the ResearchMatch.org database, and 
through emails to the Vanderbilt community
4.A Inclusion criteria
Healthy Volunteers
Free of orthostatic symptoms
No chronic medical conditions
Free of medications with the potential to influence BP
Non-smoking
Ages between 18-60
Males and females
Able and willing to provide consent
POTS Participants
Patients diagnosed with POTS by the Vanderbilt Autonomic Dysfunction Center based on the following 
stringent criteria: 1) history of daily orthostatic symptoms for at least 6 months; 2) increase in heart rate 
(HR) of at least 30 bpm with standing or a standing HR
120 bpm; 3) absence of orthostatic hypotension 
(defined as a fall in blood pressure (BP)>20/10 mm Hg); and 4) absence of conditions, such as 
dehydration, substantial weight loss, or systemic illnesses, that could provoke orthostatic intolerance
Non-smoking
Free of medications with the potential to influence BP  
24hr Urine + 
Baseline study + 
Treatment study
24hr Urine + 
Baseline study + 
Treatment study
tic sympt
tic sympt
l co
l c
will be recrui
be rec
onomic Dysfu
omic Dy
nomic Dysfun
mic Dys
mmunity
mmunity
tudy + 
nt study


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
13
Age between 18-60 years
Male and female participants are eligible
Able and willing to provide informed consent
4.B Exclusion Criteria
Overt cause for postural tachycardia (such as acute dehydration)
Significant cardiovascular, pulmonary, hepatic, or hematological disease by history or screening results
Positive urine b-hcg pregnancy test or breastfeeding
Evidence of cardiac structural disease (by clinical examination or prior echocardiogram)
Hypertension defined as a BP>145/95 (off medications) or need for antihypertensive medications
Evidence of significant conduction system delay (QRS duration >120 ms) on electrocardiogram
Known allergy to FD&C Yellow dye 6
Inability to give, or withdraw, informed consent 
Other factors which in the investigator’s opinion would prevent the participant from completing the protocol, 
including poor compliance during previous autonomic studies or an unpredictable schedule
Participants in the dose escalation phase will not be able to participate in the main study.
4.C Recruitment of Participants for Dose Escalation and Main Studies
The patients with POTS will be recruited from patients referred to the Vanderbilt University Autonomic Dysfunction 
Center.  Control participants will be recruited from healthy volunteers known to the Autonomic Dysfunction Center, 
through the ResearchMatch.org database, and through emails to the Vanderbilt community. 
Prospective participants come from several sources, including clinic patients, former patients and participants that 
read about our center on our Vanderbilt website.  We do not advertise active studies on that site but we receive 
calls asking to be seen, evaluated or studied.  If a potential participant is identified, a sample consent form is mailed 
to the participant for review.   During a follow-up telephone or email contact, the participant decides if he/she 
wishes to be screened for the study.  Clinic patients that are known to us may be offered the study and known to 
qualify in advance.  Participants enrolled in the dose escalation part of the study will not be eligible to participate in 
the main study.
All participants with POTS will have been previously evaluated with a posture study (orthostatic vital signs with 
supine and upright blood work to assess hormones). Control participants will undergo a brief history and physical 
examination to ensure that they are healthy. 
  The history will include (but not be limited to):
Framingham risk factors (age, gender, smoking, hypertension, dyslipidemia)
Metabolic diseases (metabolic syndrome, polycystic ovary syndrome, diabetes)
Inflammatory diseases (e.g., rheumatoid arthritis)
Review of medication
Date that last menstrual period started (if female).
The physical examination will include (at minimum):
Height
Weight
Orthostatic vital signs (HR and BP)
EKG
Complete blood count
Metabolic panel
4.D Retention Strategies
Follow-up.  Study participation will be complete following the inpatient evaluation.  There will be no further study 
follow-up.
Record retention. Study records will be kept for at least 7 years following the publication or presentation of the 
data collected as part of this study. 
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
14
4.E Data Elements-Dose Escalation Study
A dose escalation study will be conducted prior to the main study. A cohort consisting of one healthy 
volunteer and one patient with POTS will be administered a dose of 50mg carbidopa every 6 hours for a 
total of five doses. If this dose is well tolerated, a second cohort will be given five doses of carbidopa 
100mg with 6 hours between doses. If this dose is well tolerated, a final cohort will take the proposed 
dose of 200mg carbidopa every 6 hours for five doses. A minimum of 9 days is needed to complete the 
study with 2 nights on the CRC for the active compound and 2 nights for the placebo.
Pre-study assessments consist of 1) 12-lead ECG; 2) complete blood count (CBC:WBC, Hgb, PCV, Plt-
Ct, RBC, MCV, MCH, MCHC, RDWSD, RDW, Neut, Lym, Monocy, Eos, Baso) with platelets; 3) 
chemistry panel (CMP: Na, K, Cl, CO2, BUN, Creat, Gluc, Ca, Tprot) including albumin, total bilirubin, 
alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic 
transaminase (SGPT) to evaluate liver function; and 4) plasma carbidopa.
Participants will be provided a 200 mEq/day sodium diet, free of methylxanthines and low in 
monoamines, by the kitchen of the Clinical Research Center (CRC).
After achieving sodium balance on the study diet over 2-3 days, participants will collect urine over 24hr,
starting at 0700hr, for baseline assessment of sodium, potassium and catecholamines and to confirm 
adherence to the study diet. 
Participants will be admitted to the CRC that afternoon or evening.
In the morning, while still supine and NPO after the overnight sleep, HR and BP will be recorded with a 
Dinamap electrocardiographic and BP (brachial cuff) recorder, and blood will be drawn for a basic 
metabolic panel, fractionated catecholamines, aldosterone and plasma renin activity. The participants
will then stand for 10 minutes or for as long as they are able to tolerate. They may sit for short intervals if 
necessary.  HR and BP will be measured at 1, 3, 5, and 10 minutes of standing, and an upright blood 
sample will be collected at 10 minutes for catecholamines, plasma renin activity, and aldosterone.
The participants will be asked to void while recumbent, if able, or after the upright measurements, to end 
the first 24hr urine collection. Another 24hr urine collection will then be started for analysis of sodium, 
potassium and creatinine.
Treatment A (carbidopa or placebo) will be given orally following the void, at approximately 0700hr. 
Additional doses will be taken every 6 hours with the last dose at 0700hr the following morning. BP and 
HR will be measured and plasma carbidopa will be measured 2 hours after each dose. Participants will 
remain on the CRC for monitoring.
In the next morning, supine and standing HR and BP will be recorded with a Dinamap recorder, and the 
participants will be asked to void and collect the urine to end the 2nd 24hr urine collection. 
The final dose of study medication (carbidopa or placebo) will be given orally following the void, at 
approximately 0700hr.
Supine HR and BP will be measured by Dinamap and supine blood samples will be collected hourly for 
4 hours after the 5th dose and at 8 hours after the treatment.  Participants must rest supine for at least 
30 minutes before each blood draw.  These samples will be analyzed for catecholamines (all samples), 
and plasma renin activity and aldosterone (only at 2 hr after treatment). In addition, a basic metabolic 
panel will be run for the 4-hour and 8-hour samples.
Plasma carbidopa will be measured at 2hr, 4hr and 8hr after the final dose.
As part of the dose escalation assessment, the 12-lead ECG, CBC and Comprehensive Metabolic Panel 
will be repeated 2hr after the 5th dose.
At 2 hours after the 5th dose, participants will stand for 10 minutes for upright BP and HR measurements 
and collection of an upright blood sample, as described above.  Participants will be asked to rate the 
severity of common orthostatic symptoms while supine and upright.
Urine will be collected for two 4-hour periods after the last dose followed by a 16-hour collection to finish 
the 24-hour cycle for analysis of sodium, potassium, catecholamines, and creatinine.
Participants may be discharged from the CRC approximately 8 hours after the last dose.
After at least 24 hours, the protocol will be repeated with treatment B (carbidopa or placebo, whichever 
was not administered during treatment A). Depending on the interval, participants will either remain on 
the study diet or re-start the diet 2-3 days before admission for the 2nd phase.  
Throughout the dosing period, participants will be monitored (HR and BP measurement, Psychiatric 
Symptom Questionnaire, and questioning by study personnel 2hr after each dose) for adverse events, 
hr.r
BP will be 
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ec


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
15
including allergic reaction, nausea, acute psychosis, worsening hypotension or tachycardia, arrhythmia, 
neuroleptic malignant syndrome, hallucinations or other psychiatric symptoms. 
4.F Schedule of Events-Dose Escalation Study
Table 1  Study Schedule-Dose Escalation
Dosing 
Regimen
Time of Dose
Monitoring/Labs
Predose
NA
24hr urine for catecholamines, sodium, potassium, creatinine 
to start 24hr prior to 1st dose; 12-lead ECG; CBC with 
platelets; chemistry panel including liver enzymes; supine and 
upright BP and HR; supine and upright plasma 
catecholamines, serum aldosterone, plasma renin activity; 
plasma carbidopa; metabolic panel; start a 2nd 24hr urine for 
catecholamines, sodium, potassium, creatinine
Dose #1
0700
0900: supine BP and HR; Psychiatric Symptom 
Questionnaire; monitoring; plasma carbidopa
Dose #2
1300
1500: supine BP and HR; Psychiatric Symptom 
Questionnaire; monitoring; plasma carbidopa
Dose #3
1900
2100: supine BP and HR; Psychiatric Symptom 
Questionnaire; monitoring; plasma carbidopa
Dose #4
0100
0300: supine BP and HR; Psychiatric Symptom 
Questionnaire; monitoring; plasma carbidopa
Pre-Dose #5
0645
Supine and upright BP and HR; finish 24hr urine and start 4hr 
urine for catecholamines, sodium, potassium, creatinine
Dose #5
0700
0800: supine BP and HR; plasma catecholamines
0900: supine and upright BP and HR; 12-lead ECG; CBC with 
platelets; chemistry panel including liver enzymes; Psychiatric 
Symptom Questionnaire; Orthostatic Symptom Questionnaire; 
monitoring; plasma carbidopa; supine and upright plasma 
catecholamines, serum aldosterone, plasma renin activity
1000: supine BP and HR; plasma catecholamines
1100: supine BP and HR; metabolic panel; plasma 
catecholamines; plasma carbidopa; restart 4hr urine for 
catecholamines, sodium, potassium, creatinine
1500: supine BP and HR; metabolic panel; plasma 
catecholamines; plasma carbidopa; start 16hr urine for 
catecholamines, sodium, potassium, creatinine
0900:
0900:
P a
P 
e; monit
mon
ne BP and 
BP an
nnaire; mon
naire; m
ne and uprig
and up
ne for catec
for cat
0800: supin
00: su
su
s
platele
plate
Sym
G; 
r enzym
enzym
ht plasma
plasma
e, , plasma
plasm
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anel; start 
start
assium, c
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Psychiatri
Psychiat
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 HR; 
HR Psyc
Psyc
onitoring; p
nitoring; p
nd HR
nd HR
or


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
16
Table 2. Study Day Description-Dose Escalation
Day
Treatment
Time
Assessments for 
Tolerability
Obtain Consent
History & 
Physical
Pregnancy Test
Study Diet
Carbidopa or 
Placebo
Blood Draw
HR/BP
Urine
Pre-Study
X
X
X
X
X
-3, -2
X
Start study diet
-1
0700
X
Start 24hr urine #1
1
0645
X
X
X End & restart 24hr urine
A 0700, 1300, 1900
X
Doses 1, 
2, 3
Continue 24hr urine #2
0900, 1500, 2100
X
X
X
X Continue 24hr urine #2
2
0100
X
Dose 4
Continue 24hr urine #2
0300
X
X
X
X Continue 24hr urine #2
0645-0700
X
Dose 5
X End 24hr, start 4hr urine #1
0800
X
X
X Continue 4hr urine #1
0900
X
X
X
X Continue 4hr urine #1
1000
X
X
X Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr
urine #2
May be 
discharged
1500
X
X
X End 4hr urine #2 & start 16hr 
3(washout 
day)
0700
X
End 16hr urine
4
0700
X
Start 24hr urine 
5
0645
X
X
X End & restart 24hr urine
B 0700, 1300, 1900
X
Doses 1, 
2, 3
Continue 24hr urine #2
0900, 1500, 2100
X
X
X
X Continue 24hr urine #2
6
0100
X
Dose 4
Continue 24hr urine #2
0300
X
X
X
X Continue 24hr urine #2
0645-0700
X
Dose 5
X End 24hr, start 4hr urine #1
0800
X
X
X Continue 4hr urine #1
0900
X
X
X
X Continue 4hr urine #1
1000
X
X
X Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr
urine #2
1500
X
X
X End 4hr urine #2 & start 16hr 
7
0700
End 16hr urine
00
X
on
Continu
X
on
X
X
X
X


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
17
4.G Data Elements-Main Study
A minimum of 9 days is needed to complete the study with 2 nights on the CRC for the active compound 
and 2 nights for the placebo.
Participants will be provided a 200 mEq/day sodium diet, free of methylxanthines and low in 
monoamines, by the kitchen of the Clinical Research Center (CRC).
After achieving sodium balance on the study diet over 2-3 days, participants will collect urine over 24hr 
starting at 0700hr, for baseline assessment of sodium, potassium and catecholamines and to confirm 
adherence to the study diet. 
Participants will be admitted to the CRC that afternoon or evening.
In the morning, while still supine and NPO after the overnight sleep, HR and BP will be recorded with a 
Dinamap electrocardiographic and blood pressure (brachial cuff) recorder, and blood will be drawn for a 
basic metabolic panel, fractionated catecholamines, aldosterone and plasma renin activity. The 
participants will then stand for 10 minutes or for as long as they are able to tolerate. They may sit for 
short intervals if necessary.  HR and BP will be measured at 1, 3, 5, and 10 minutes of standing, and an 
upright blood sample will be collected at 10 minutes for catecholamines, plasma renin activity, and 
aldosterone.
The participants will be asked to void while recumbent, if able, or after the upright measurements, to end
the first 24hr urine collection. Another 24hr urine collection will then be started for analysis of sodium, 
potassium and creatinine. This may take the form of one 24 hr sample or two 4 hr collection samples 
followed by a 16 hr sample collected from approximately 3 pm to 7am the following morning. The second 
schedule will facilitate comparison to urinary excretion after the final dose.
Treatment A (Carbidopa 200mg or placebo) will be given orally following the void, at approximately 
0700hr. Additional doses will be taken every 6 hours with the last dose at 0700hr the following morning.
BP and HR will be measured 2 hours after each dose. Participants will remain on the CRC for 
monitoring.
In the next morning, supine and standing HR and BP will be recorded with a Dinamap recorder, and the 
participants will be asked to void and collect the urine to end the 2nd 24hr urine collection. 
The final dose of study medication (Carbidopa 200mg or placebo) will be given orally following the void, 
at approximately 0700hr.
Supine HR and BP will be measured by Dinamap and supine blood samples will be collected hourly for 
4 hours after the 5th dose and at 8 hours after the treatment.  Participants must rest supine for at least 
30 minutes before each blood draw.  These samples will be analyzed for catecholamines (all samples), 
carbidopa (at 2, 4 and 8hr) and plasma renin activity and aldosterone (only at 2 hr after treatment).  In 
addition, a basic metabolic panel will be run for the 4-hour and 8-hr samples. 
At 2 hours after the last dose, participants will stand for 10 minutes for upright BP and HR 
measurements and collection of an upright blood sample, as described above.  Participants will be 
asked to rate the severity of common orthostatic symptoms while supine and upright.
Urine will be collected for two 4-hour periods after the last dose followed by a 16-hr collection to finish 
the 24-hour cycle for analysis of sodium, potassium, catecholamines, and creatinine.  
Participants may be discharged from the CRC approximately 8 hours after the last dose.
After at least 24 hours, the protocol will be repeated with treatment B (Carbidopa 200 mg or placebo, 
whichever was not administered during treatment A). Depending on the interval, participants will either 
remain on the study diet or re-start the diet 2-3 days before admission for the 2nd phase.
colle
olle
severity o
severity 
llected for
lected fo
ycle for a
ycle for a
ay be
ay b
n
the ur
e u
dopa 200m
pa 200m
d by Dinamap
by Dina
hours after 
ours a
draw.  These
aw.  The
and plasma r
d plasma
c panel will b
c panel will
dose
ose, partic
par
ction of 
on
co
he upright
e uprigh
be started f
e started
mple or two
mple or tw
o 7am the 
7am the 
he final dos
e final dos
orally follo
orally follo
ith the last 
h the last 
e. Participa
Particip
BP will 
BP w
e t


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
18
4.H Schedule of Events-Main Study
Table 3 Study Schedule-Main Study
Dosing 
Regimen
Time of Dose
Monitoring/Labs
Predose
NA
24hr urine for catecholamines, sodium, potassium, creatinine 
to start 24hr prior to 1st dose; supine and upright BP and HR; 
supine and upright plasma catecholamines, serum 
aldosterone, plasma renin activity; metabolic panel; start 
another urine collection over 24 hr for catecholamines, 
sodium, potassium, creatinine
Dose #1
0700
0900: supine BP and HR 
Dose #2
1300
1500: supine BP and HR
Dose #3
1900
2100: supine BP and HR
Dose #4
0100
0300: supine BP and HR
Pre-Dose #5
0645
Supine and upright BP and HR; finish 24hr urine and start 4hr 
urine for catecholamines, sodium, potassium, creatinine
Dose #5
0700
0800: supine BP and HR; plasma catecholamines
0900: supine and upright BP and HR; plasma carbidopa; 
Orthostatic Symptom Questionnaire; supine and upright 
plasma catecholamines, serum aldosterone, plasma renin 
activity
1000: supine BP and HR; plasma catecholamines
1100: supine BP and HR; metabolic panel; plasma 
catecholamines; plasma carbidopa; restart 4hr urine for 
catecholamines, sodium, potassium, creatinine
1500: supine BP and HR; metabolic panel; plasma 
catecholamines; plasma carbidopa; start 16hr urine for 
catecholamines, sodium, potassium, creatinine
g
cholam
ola
ne BP and 
BP and
pine and up
e and
static Symp
atic Sy
sma catecho
ma cate
activity
tivity
1000: sup
1000: s
1100: s
1100: s
cate
t
ca
 upri
upr
mines
ines, , se
se
metabolic 
metabolic 
hr for cate
hr for ca
HR
HR
nd HR
nd HR
t BP and
BP a
ine
ine


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
19
5. Data and Safety Monitoring Plan  
Table 4. Study Day Description-Main Study
Day
Treatment
Time
Obtain Consent
History & 
Physical
Pregnancy Test
Study Diet
Carbidopa or 
Placebo
Blood Draw
HR/BP
Urine
Pre-Study
X
X
X
-3, -2
X
Start study diet
-1
0700
X
Start 24hr urine #1
1
0645
X
X
X
End & restart 24hr of urine
collection
A
0700, 1300, 1900
X
Doses 1, 
2, 3
Continue  urine collection
0900, 1500, 2100
X
X
Continue urine collection
2
0100
X
Dose 4
Continue urine collection
0300
X
X
Continue urine collection
0645-0700
X
Dose 5
X
End 24hr of urine collection, start 
4hr urine #1
0800, 0900, 1000
X
X
X
Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr urine 
#2
May be 
discharged
1500
X
X
X
End 4hr urine #2 & start 16hr 
urine
3(washout 
day)
0700
X
End 16hr urine
4
0700
X
Start 24hr urine 
5
0645
X
X
X
End & restart 24hr of urine
collection
B
0700, 1300, 1900
X
Doses 1, 
2, 3
Continue urine collection
0900, 1500, 2100
X
X
Continue urine collection
6
0100
X
Dose 4
Continue urine collection
0300
X
X
Continue urine collection
0645-0700
X
Dose 5
X
End 24hr of urine collection, start 
4hr urine #1
0800, 0900, 1000
X
X
X
Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr urine 
#2
1500
X
X
X
End 4hr urine #2 & start 16hr 
urine
7
0700
End 16hr urine
1900
500, 2100
X
coll
Conti
X
Dose 5


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
20
The NINDS has reviewed the risk associated with this study, and the following safety monitoring will be 
implemented:
The Study Chair will appoint an NINDS approved Independent Medical Monitor (IMM) to review all adverse 
events that are serious, unexpected, and possibly/probably/definitely related to the study intervention in real 
time.
The IMM will also review cumulative AEs. The frequency of review of cumulative AEs will be determined by the 
IMM in conjunction with the Study Chair and will occur at least once every 12 months.
The site’s Primary Investigator and the research team (co-Investigators, research nurses, clinical trial 
coordinators, and data managers) are responsible for identifying adverse events. Aggregate report- detailed by 
severity, attribution (expected or unexpected), and relationship to the study drug/study procedures – will be 
available from the DMCC for site review.  Adverse events will be reviewed regularly by the research team.   A 
separate report detailing protocol compliance will also be available from the DMCC for site review on a monthly 
basis. 
Adverse events will be monitored on an ongoing basis by Drs. David Robertson and Emily Garland.  
 
 RN will be responsible for tracking adverse events in this study.  Any adverse event of a serious or 
greater nature will be reviewed immediately with the P.I.  Drs Robertson and Garland and 
 will 
convene monthly to discuss the progress of the study and any issues concerning data collection and safety.
  
Serious adverse events will be reported in writing to the Vanderbilt IRB, with copies to the CRC Advisory 
Committee, within 24 hours of occurrence.  All study adverse events will be summarized once a year, as part of 
the annual review report to the IRB.
  
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 
4 = Life-threatening or disabling adverse event
5 = Death related to adverse event
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.”
5.A Study Oversight
The study protocol will be reviewed and approved by the National Institutes of Health (NIH) before submission to 
individual center IRB’s for approval. Participant enrollment may only begin with IRB approved consent forms.
This is a phase II study that meets the federal definition of moderate risk.
The Study Chair has primary oversight responsibility of this clinical trial. The Autonomic Consortium will review
accrual, patterns and frequencies of all adverse events, and protocol compliance at least every 6 months. 
5.B Definitions and Standards 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an unfavorable and unintended 
sign, symptom or disease associated with a participant’s participation in a Rare Diseases Clinical Research 
Network study.”
disab
sa
adverse e
adverse 
state his
state his
re pe
re 
owing in
ing i
dy procedur
procedu
o the followin
he follo
al limits
imit
and mild in n
d mild i
ome interven
me inter
ing adv
ng
ve
C fo
C f
ertson and 
tson and
Any adver
Any adve
son and Ga
n and G
ues concer
es concer
Vanderbilt 
Vanderbilt
rse events 
 events


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
21
Serious adverse events include those events that:  “result in death; are life-threatening; require inpatient 
hospitalization or prolongation of existing hospitalization; create persistent or significant disability/incapacity, or a 
congenital anomaly/birth defects.” 
An unexpected adverse event is defined as any adverse experience…the specificity or severity of which is not 
consistent with the risks of information described in the protocol. Expected adverse events are those that are 
known to be associated with or have the potential to arise as a consequence of participation in the study
All reported adverse events will be classified using the current version of the Common Terminology Criteria for 
Adverse Events (CTCAE) developed and maintained by CTEP at National Cancer Institute.
5.C Expected/Known Risks/Discomforts/Adverse Events Associated with Study 
Intervention and Procedures: Definition of Expected Adverse Events 
Study Drug/Intervention: Carbidopa / Placebo
Drug Information for STUDY DRUG
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in 
water, with a molecular weight of 244.3. It is designated chemically as (—)-L- hydrazino- -methyl- -(3,4-
dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10H14N2O4•H2O, and its structural formula 
is:
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3.
LODOSYN (Carbidopa) tablets contain 25 mg of carbidopa. Inactive ingredients are cellulose, FD&C Yellow 6, 
magnesium stearate and starch.
Human Toxicity/ Adverse Events (adapted from package insert)
Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. 
The only adverse reactions that have been observed have been with concomitant use of carbidopa with other drugs 
such as levodopa, and with carbidopa-levodopa combination products.  Common adverse events with the 
carbidopa-levodopa combination include abnormal body movements and nausea.  Less common adverse effects 
are psychotic episodes (periods of confused thinking which can include hearing voices, seeing things that are not 
real, believing things that are not true and/or strange behavior), depression and dementia (loss of mental ability 
severe enough to cause problems with normal activities of daily living). Rarely, there is an allergic reaction to the 
FD&C Yellow 6 dye. The dose in this study is a much higher dose than used in clinical practice, and there may be 
additional side effects that are not known at this time.  This medication has never been used at this dose or 
frequency.
Study Procedures:
Venipuncture:  The vein in which the needle has been inserted to draw blood may become sore and red.  A 
temporary “black and blue mark” may develop, and rarely fainting may occur.
5.D Reporting Timeline
vents (ada
vents (ada
demonstr
demonst
ns that 
ns that
with
wit
rous ca
25 mg of
ne comp
ydrazino
H14N2O4


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
22
Withi 24 hours (of learning of the event), investigators must report any reportable Serious Adverse Event (SAE) 
that:
o
Is considered life-threatening/disabling or results in death of participant
-OR- 
o
Is Unexpected/Unanticipated 
Investigators must report all other reportable SAEs within 5 working days (of learning of the event).
All other (suspected) reportable AEs must be reported to the RDCRN within 20 working days of the notification 
of the event or of the site becoming aware of the event.
Local institutional reporting requirements to IRBs, any Vanderbilt Institute for Clinical and Translational 
Research/Clinical Research Center (VICTR/CRC) oversight committee and the FDA, if appropriate, remain the
responsibility of the site investigator and the Study Chair.
5.E RDCRN Adverse Event Data Management System (AEDAMS) 
Upon entry of a serious adverse event by a site investigator, the DMCC created Adverse Event Data Management 
System (AEDAMS) will immediately notify the Study Chair and the Independent Medical Monitor.  
The Study Chair is responsible for notifying the appropriate NINDS staff.
Serious adverse events: The site investigator determines causality (definitely not related, probably not related, 
possibly related, probably related, definitely related) of the adverse event. The IMM will also review the SAE 
incident report.
The IMM may request further information if necessary and possibly suggest changes to the protocol or consent 
form to the NINDS as a consequence of  adverse events.  The Adverse Event Data Management System 
(AEDAMS) maintains audit trails and stores data (and data updated) and communication related to any adverse 
event in the study.  
Non-serious expected adverse events: Except those listed above as immediately reportable, non-serious expected 
adverse events  that are reported to or observed by the investigator or a member of his research team will be 
submitted to the DMCC in a timely fashion (within 20 working days). The events will be presented in tabular form 
and given to the IMM at least once every 12 months or as requested. Local site investigators are also required to 
fulfill all reporting requirements of their local institutions.
The DMCC will post aggregate reports of all adverse events (serious/not serious and expected, unexpected) for site 
investigators and IRBs.
5.F Study Discontinuation
The NIH and local IRB's (at their local site) have the authority to stop or suspend this trial at any time. This study
may be suspended or closed:
For safety concerns
For other reasons as determined by the NIH or FDA
5.G Participant Discontinuation 
An intent to treat approach will be used. All data acquired prior to termination for the reasons outlined below will be 
included in the primary analysis unless the participant withdraws consent. Every effort will be made to conduct a 
final study visit with the participant, and participants will be followed clinically until, if applicable, all adverse events 
resolve. 
Withdrawal of consent
Withdrawal by the investigator
Noncompliance to study diet and or urine collections
Unanticipated reaction to study drug / placebo
uation
uation
at their loc
t their lo
osed:
osed:
ns
isted abov
ted abo
y the investig
he inves
n 20 working
20 worki
months
nths or as 
or 
al institutions
stitution
s of all adver
of all adv
ical M
cal M
y not related
not rela
The IMM w
The IMM w
y suggest
suggest
Adverse Ev
dverse Ev
pdated) an
pdated) an


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
23
5.H Data Quality and Monitoring Measures 
As much as possible data quality is assessed at the data entry point using intelligent on-line data entry via visual 
basic designed screen forms. Data element constraints, whether independent range and/or format limitations or 
‘relative’ referential integrity limitations, can be enforced by all methods employed for data input. QA reports assess 
data quality post-data entry. As we note, data quality begins with the design of the data collection forms and 
procedures and incorporates reasonable checks to minimize transcription and omission errors.  Of the more 
important quality assurance measures are the internal validity checks for reasonableness and consistency. 
Data Monitoring: The RDCRN DMCC identifies missing or unclear data and generates a data query to the 
consortium administrator contact. 
Data Delinquency Tracking: The Data Management and Coordinating Center will monitor data delinquency 
on an ongoing basis.
6.  Statistical Considerations
Individual data will be reviewed for the Dose Escalation Study with the post-dose data compared to pre-dosing 
data. The data for each cohort will be summarized for review by Dr. David Robertson and the IMM of this study.The 
primary outcome is the urinary sodium concentration normalized to creatinine. Differences in urinary sodium in 
samples (1) collected at baseline vs. those collected following treatment (time effect) and (2) collected after placebo 
vs. carbidopa (treatment effect) will be assessed using a paired t-test and Wilcoxon signed-rank test.  Differences 
between the patient and control groups (group effect) will be assessed using a student’s t-test and a Mann-Whitney 
U test.  Similar methods will be used to compare secondary outcome measures, such as BP, HR, plasma and 
urinary catecholamines, plasma renin activity, plasma aldosterone, and plasma sodium. All data analyses will be 
performed using SPSS 18.0 (SPSS, Chicago, IL) or STATA 8.2 (StataCorp, College Station, TX).  All statistical 
tests will be two-sided. A mixed-effects model will be developed to describe the time, medication and group effects. 
Sample Size Calculation. Based on our preliminary findings of a standard deviation for urinary sodium excretion of 
30 mEq/g creatinine, a sample size of 16/group (32 total) will have 80% power to detect a difference in group 
means (control vs. POTS) of 31 mEq/g creatinine with a 0.05 two-sided significance level. To allow for participant
drop-out prior to study completion, we will plan to obtain informed consent from 35 participants in total (18 POTS, 
17 healthy controls). 
Randomization procedures were performed by 
 and the results provided to Vanderbilt’s 
Investigational Pharmacy. Prior to admission, the pharmacy is notified whether the participant is a patient or healthy 
volunteer and the Investigational Pharmacist determines the treatment order (placebo or carbidopa first). At the end
of the study, the blinding will be broken by the Vanderbilt Investigational Pharmacy and the order of agents will be 
revealed to the investigators and to the participants, if they so request.
7. Data Management
The investigators, research personnel and nursing staff at the CRC will collect the majority of the data at the 
bedside in real time.  Data will be handwritten on CRFs provided by Emily Garland, PhD.  Routine labs are sent to 
brok
bro
and to th
and to th
dings
ngs
tal) will ha
will h
with a 0.05 tw
h a 0.05 
o obtain infor
btain inf
med by 
ed by 
dmission, the
dmission, th
harmacist d
armacist 
en by th
n 
pa
co
n and th
and t
fferences i
erences 
effect) and
ffect) an
Wilcoxon sig
ilcoxon s
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and plasma
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StataCorp, 
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o descri
of a s
of a s


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
24
the hospital laboratory for analysis.  Special study specific labs (ex: catecholamines) are sent to the GCRC Core 
Lab for analysis.  Laboratory data will be obtained from Vanderbilt Medical Center’s online medical chart system 
(StarPanel) and from the GCRC Core Laboratory website, both of which are password protected and only
authorized personnel have access.  After all data points have been retrieved, a member of the research team will 
enter the data into the DMCC database, which is also password protected and only accessible to authorized 
personnel.  Data analysis will be performed routinely for periodic review. Hard copies of the CRFs will be 
maintained in the patient’s research chart in a locked cabinet. Study participation will be complete following the 
inpatient evaluation.  There will be no further study follow-up.  Study records will be kept for at least 7 years 
following the publication or presentation of the data collected as part of this study. 
All study data will be collected via systems created in collaboration with the RDCRN Data Management and 
Coordinating Center and will comply with all applicable guidelines regarding patient confidentiality and data 
integrity.   
7.A Registration 
Registration of participants on this protocol will employ an interactive data system in which the clinical site will attest 
to the participant’s eligibility as per protocol criteria and obtain appropriate informed consent. IRB approval for the 
protocol must be on file at the DMCC before accrual can occur from the clinical site.
The DMCC will use a system of coded identifiers to protect participant confidentiality.  Each participant enrolled will 
be assigned a local identifier by the enrollment site.  This number can be a combination of the site identifier 
(location code) and a serial accession number.  Only the registering site will have access to the linkage between 
this number and the personal identifier of the participant.  When the participant is registered to participate in the 
study, using the DMCC provided web-based registration system, the system will assign a participant ID 
number.  Thus each participant will have two codes: the local one that can be used by the registering site to obtain 
personal identifiers and a second code assigned by the DMCC.  For all data transfers to the DMCC both numbers 
will be required to uniquely identify the participant.  In this fashion, it is possible to protect against data keying 
errors, digit transposition or other mistakes when identifying a participant for data entry since the numbers should 
match to properly identify the participant.  In this fashion, no personal identifiers would be accessible to the DMCC. 
7.B Data Entry
Data collection for this study will be accomplished with online electronic case report forms.  Using encrypted 
communication links, on-line forms will be developed that contain the requisite data fields.   
7.C Laboratory data flow
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 the PI, other staff members of the Autonomic Dysfunction Center, and their collaborators.  
All data and research specimens will be maintained by David Robertson, M.D. following study termination for an 
indeterminate period of time. 
Laboratory specimens, especially for catecholamine determination, are kept in the Core Lab.  Specimens are 
secured in a frozen state in a locked –70° freezer.  The results are entered into the CRC Core Lab password-
protected database.
8.  Human Participants
All patients who contact us with symptoms of orthostatic intolerance or tachycardia are in theory eligible for this 
study.   Most of them find us because we have a website.  If they complete the screening process (IRB #030751) 
and meet the criteria for the study, i.e. have difficulty maintaining a standing posture, have classic symptoms 
(palpitations, dizziness, difficulty thinking, chest tightness) while upright or have heart rate changes and high 
plasma catecholamines on standing, they may be eligible to participate.  
The participants are screened on the CRC where pertinent heart rate, blood pressure, history and laboratory data 
are obtained to make sure that they are appropriate and can tolerate this study. Study personnel will be 
experienced in the conduct and completion of patient-oriented investigations.
int
in
maintai
mainta
he PI, othe
he PI, othe
ecimens w
ecimens w
me. 
me. 
fa
ng a 
on, no p
plished with o
hed wit
e developed 
develop
o the pass
the pass
ned 
e
whic
 consen
.
dentiality.
combin
e will hav
e participa
the system
e that ca
C. For a
hion, 


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
25
This clinical trial will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with Good Clinical Practice and all applicable regulatory requirements.
8.A Human participants involvement and characteristics 
Inclusion of vulnerable groups: 
No ethnic group is targeted or excluded. 
Inclusion of Women. To the extent possible, patient and control groups will include approximately equal numbers 
of males and females. However, postural tachycardia syndrome is far more common in women than in men. Based 
upon prior experience, we anticipate a patient population that is approximately 80% female and 20% male 
Inclusion of Minorities. The ethnic composition of Nashville is ~79.4% non-Hispanic white American, 15.6% black 
American, 1.7% Asian and Pacific Islander, 0.3% American Indian and Alaska Native, and 3% Hispanic.  In the 
literature on postural tachycardia syndrome, breakdown of study participants by race is frequently not reported.  No 
one to our knowledge has reported a race-based difference in the frequency of this category of illness. However, 
investigators who see substantial numbers of tertiary referrals of patients with the postural tachycardia syndrome, 
including ourselves, encounter this disease only rarely in African-Americans, and believe this may reflect a true 
difference in susceptibility. Through the alliance between Vanderbilt and the historically African-American Meharry 
Medical College, in Nashville, we will attempt to enrich our study population by recruiting African-American patients 
for evaluation at our institution. 
8.B Informed consent
Written informed consent will be obtained from each participant before any study-specific procedures or
assessments are done and after the aims, methods, anticipated benefits, and potential hazards are explained.  The 
participant’s willingness to participate in the study will be documented in writing in a consent form, which will be 
signed by the participant with the date of that signature indicated.  The investigator will keep the original consent 
forms and signed copies will be given to the participants.  It will also be explained to the participants that they are 
free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future 
treatment.  Written and/or oral information about the study in a language understandable by the participant will be 
given to all participants.
See appendix 1a &1b
8.C Potential risks
1.
There is the inconvenience of having to sleep on the CRC for several nights.
2.
Intravenous catheter placement and blood sampling can cause bruising, pain and infection.
3.
Collecting urine can be inconvenient and embarrassing.
4.
Blood pressure measurements with a cuff on the arm can be uncomfortable.  
5.
Drawing blood for analysis can cause discomfort or bruising. 
6.
Standing upright may cause lightheadedness, blurred vision, rapid heartbeat, headache and nausea. 
7.
Carbidopa – only reported to have adverse effects when it is given with the drug levodopa for Parkinson’s 
disease.  Less common adverse effects are allergies, psychotic episodes, depression and dementia.
However, the dosage used in this study is higher than typically administered. We will therefore do a dose 
escalation study to assess the tolerability of the 200mg carbidopa dose that we propose to use in the main 
study.
8.
Consuming a sodium- and caffeine-controlled diet that needs to be picked up at the CRC might be 
inconvenient.  If caffeine intake is stopped suddenly, participants might have headaches and fatigue for a 
few days.  
ce
placeme
placem
n be inconv
n be incon
measureme
measurem
or analys
or analy
ay
ay
ndica
dic
ts.  It will 
It wil
aw from the 
from th
the study in 
e study 
of having
f having
nt an
nt
cat
ca
e postura
postura
and believ
d believ
historically
istoricall
n by recrui
n by recru
before any 
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umented
ted.  T
ted.  


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8.D Protection against risk
Due to the dosage of carbidopa proposed for the main study, an IND (#108723) has been obtained by Dr. David 
Robertson. All procedures have been used previously by the staff of the CRC or ADC, and risks will be minimized 
by using trained, well-qualified personnel.  
8.E Potential benefits of the proposed research to the participants and others
Although we cannot guarantee any benefit to the individuals who participate in this study, we hope to obtain 
knowledge from this study that will help us to better understand the causes of problems involving blood pressure 
and heart rate.
8.F Importance of the knowledge to be gained
It is possible that this study might provide insight into the effectiveness of a potential treatment for their disorder and 
provide either direct or indirect benefit to their medical care.
8.G Confidentiality
As part of the Vanderbilt application, the principal investigator signs the following statement of assurance. 
PRINCIPAL INVESTIGATOR’S ASSURANCE STATEMENT
I certify that the information provided in this application is complete and accurate.
I understand that as Principal Investigator, I have ultimate responsibility for the conduct of the study, the ethical performance 
of the project, the protection of the rights and welfare of human participants, and strict adherence to the study protocol and any 
stipulations imposed by the Vanderbilt University Institutional Review Board.
I understand that, should I use the project described in this application as a basis for a proposal for funding (either intramural or 
extramural), it is my responsibility to ensure that the human participants' involvement as described in the funding proposal(s), 
is consistent in principle, to that contained in this application. I will submit modifications and/or changes to the IRB as 
necessary, in the form of an amendment, to ensure these are consistent.   
I agree to comply with all VU policies and procedures, as well as with all applicable federal, state, and local laws regarding the 
protection of human participants in research, including, but not limited to:
Ensuring all investigators and key study personnel have completed the VU human participants training program;
Ensuring the project is conducted by qualified personnel following the approved IRB application and study protocol;
Implementing no changes in the approved IRB application, study protocol, or informed consent document without prior 
IRB approval in accordance with VU IRB policy (except in an emergency, if necessary to safeguard the well-being of a 
human participant, and will report to the IRB within 5 days of such change);
Obtaining the legally effective informed consent from human participants or their legally responsible representative, using 
only the currently approved date-stamped informed consent documents, and providing a copy to the participant, if 
applicable.
Promptly report to the IRB, Data Safety and Monitoring Boards, sponsors and appropriate federal agencies any adverse 
experiences and all unanticipated problems involving risks to human participants or others that occur in the course of the 
research in accordance with Vanderbilt University IRB Policies and Procedures.
If unavailable to conduct this research personally, as when on sabbatical leave or vacation, I will arrange for another 
investigator to assume direct responsibility for the study.  Either this person is named as another investigator in this 
application, or I will notify the IRB of such arrangements;
Promptly providing the IRB with any information requested relative to the project; 
Promptly and completely complying with an IRB decision to suspend or withdraw approval for the project; 
Obtaining Continuing Review approval prior to the date the approval for the study expires.  I understand if I fail to apply 
for continuing review, approval for the study will automatically expire, and all study activity must cease until IRB 
approval is granted;
Maintain accurate and complete research records, including, but not limited to, all informed consent documents for 3 years 
from the date of study completion;
Maintain any authorization documents to use or disclose PHI for 6 years from the date authorization is obtained; and
 a
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n as 
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RDCRN ARD #6101
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Fully informing the VU IRB of all locations in which human participants will be recruited for this project and being 
responsible for obtaining and maintaining current IRB approvals/letters of cooperation and Federal Wide Assurances 
(FWAs), when applicable.
_______________________________________________________________________________________
Principal Investigator’s Signature     Date
By my signature, I certify that I have evaluated this research application for soundness of research design and scientific 
merit in accordance with departmental policy and the adequacy of facilities and resources.
_______________________________________________________________________________________
Division Chief’s Signature*      Date
_______________________________________________________________________________________
Department Chair’s Signature*      Date
*Requires one signature other than PI
8.H Financial considerations
Participants with POTS will not be monetarily compensated for their participation in this study.
Healthy control 
participants will be compensated $450 in the dose escalation study and $400 in the main study for their 
inconvenience and time involved in participating in this study.
The investigator has no financial interest or 
compensation from the outcomes of the study.
8.I Conflict of interest
There are no known conflicts of interest between study participants, research personnel and other entities 
regarding the conduction of the study.
particip
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The i
n


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9.  References
1. Ball SG, Lee MR (1977) The effect of carbidopa administration on urinary sodium excretion in man. Is dopamine an 
intrarenal natriuretic hormone? Br J Clin Pharmacol 4:115-119
2. Barendregt JN, Muizert Y, van Nispen tot Pannerden LL, Chang PC (1995) Intrarenal production of dopamine and 
natriuresis following DOPA and saline infusions in healthy human volunteers. J Hum Hypertens 9:187-194
3. Barthelmebs M, Mbou P, Stephan D, Grima M, Imbs JL (1993) Renal dopamine excretion in healthy volunteers after 
oral ingestion of L-dopa. Fundam Clin Pharmacol 7:11-16
4. Cuche JL, Prinseau J, Selz F, Ruget G, Tual JL, Reingeissen L, Devoisin M, Baglin A, Guedon J, Fritel D (1985) Oral 
load of tyrosine or L-dopa and plasma levels of free and sulfoconjugated catecholamines in healthy men. 
Hypertension 7:81-89
5. Durso R, Evans JE, Josephs E, Szabo G, Evans B, Fernandez HH, Browne TR (2000) Variable absorption of 
carbidopa affects both peripheral and central levodopa metabolism. J Clin Pharmacol 40:854-860
6. Gluck Z, Jossen L, Weidmann P, Gnadinger MP, Peheim E (1987) Cardiovascular and renal profile of acute 
peripheral dopamine1-receptor agonism with fenoldopam. Hypertension 10:43-54
7. Grossman E, Shenkar A, Peleg E, Thaler M, Goldstein DS (1999) Renal effects of L-DOPA in heart failure. J 
Cardiovasc Pharmacol 33:922-928
8. Hershey T, Black KJ, Hartlein J, Braver TS, Barch DM, Carl JL, Perlmutter JS (2004) Dopaminergic modulation of 
response inhibition: an fMRI study. Brain Res Cogn Brain Res 20:438-448
9. Kaufmann H, Saadia D, Voustianiouk A, Goldstein DS, Holmes C, Yahr MD, Nardin R, Freeman R (2003) 
Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 108:724-728
10. Mathur VS, Swan SK, Lambrecht LJ, Anjum S, Fellmann J, McGuire D, Epstein M, Luther RR (1999) The effects of 
fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects. 
Crit Care Med 27:1832-1837
11. Shigetomi S, Buu NT, Kuchel O (1991) Dopaminergic abnormalities in borderline essential hypertensive patients. 
Hypertension 17:997-1002
12. Stokes GS, Monaghan JC, Pillai DN (1997) Effects of carbidopa and of intravenous saline infusion into normal and 
hypertensive subjects on urinary free and conjugated dopamine. J Hypertens 15:761-768
2
an JC, Pilla
an JC, Pil
ects on urin
ects on uri
ra
ein DS, Holm
DS, Ho
ic orthostatic 
orthost
njum S, Fellm
um S, F
ceptor agonist
ptor agoni
l O (1991) D
O (1991) 
0) Vari
) Vari
acol 40:854
col 40:85
ascular and
ascular a
10:43
10:43-54
Renal effec
Renal effec
Carl JL, Perl
arl JL, Perl
n Res 20
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10.  APPENDICES
APPENDIX 1a Sample Informed Consent Form for Main Study - POTS
This informed consent applies to Participants with Postural Tachycardia Syndrome
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 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.    
1.
What is the purpose of this study? 
You are being asked to take part in this research study because you have been diagnosed with Postural 
Tachycardia Syndrome (POTS).  A chemical in the kidney called dopamine plays an important role in maintaining 
your body’s salt levels.  We will give you a drug called carbidopa that interferes with the formation of dopamine in 
the kidney, and we will measure how much salt is then excreted in your urine.  This drug has been used for many 
years at lower doses to treat Parkinson’s disease.  We will also measure your blood pressure and heart rate and 
some chemicals in your blood and urine that control them.  We will compare the effects of this drug to those of a 
sugar pill.  You will take the drug and the sugar pill on different days (Treatment A and Treatment B), but you will 
not be told which one you are taking on a given day. We expect to enroll 16 participants with POTS and 16 healthy 
volunteers.
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).  You will be asked some questions 
about your health other than POTS.  One of the investigators will explain the study to you and ask you to sign this 
consent form.  A copy of the consent form will be given to you.  Your participation is voluntary.
A minimum of 9 days will be required to complete this study.  You will need to spend 4 nights on the CRC, 2 nights 
for the active drug and 2 nights for the sugar pill.  Alternatively, you may stay as an inpatient on the CRC for the 
entire study period. On the morning after the first overnight, study day 1, we will collect pre-treatment data and then 
give you your first pill. You will take pills every 6 hours. You will need to be on the CRC so that we can measure 
your blood pressure and heart rate two hours after every dose. Studies on the second study day will last until about 
3pm.   Different parts of the study are described below.
Drug withdrawal
You must remain off any medications that could affect blood pressure, the composition of your urine, or the 
chemicals that we will measure for three days prior to the first treatment and during the entire study.  This includes 
not only your usual scheduled medications, but also other drugs that might be taken intermittently.  You should 
consult your primary care physician before stopping any drug and contact the Principal Investigator or his nurse if 
any problems occur prior to admission. Your symptoms, such as dizziness, fatigue, nausea, fainting or near 
fainting, might get worse, but they should be relieved by lying down.  If necessary, we will admit you to the hospital 
and take you off your medications there.  While you are an inpatient on the CRC, we will check your general 
condition, blood pressure and heart rate regularly to reduce any risk. 
Pregnancy test
If you are a female, we will perform a pregnancy test on a sample of your blood when you are admitted to the 
hospital for this study.  Pregnant females may not participate in this research study.  
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We will ask you to eat a standard diet with no caffeine and a controlled amount of salt for three days prior to each 
study day and during the study days.  We will provide this food to you and ask you to eat all of it and no other food.  
We will check to be sure that you are doing this by having you collect all of your urine for 24 hours and measuring 
the amount of salt in it (see below).
Urine Collection
You will collect your urine for 24 hours before administration of the first pill (active drug or sugar pill) and for the 
next 24 hours (study day 1).  After the last pill, on the second study day, you will collect samples over the first 4 
hours, from 4-8 hours, and from 8-24 hours.  The urine will be analyzed for sodium, potassium and for hormones 
that control blood pressure and heart rate.
Vital signs
Vital signs (blood pressure and heart rate) will be measured several times while you are lying down just before and 
after the treatment.  Sometimes you will be asked to stand quietly for 10 minutes for additional measurements.  A 
Dinamap, an automated blood pressure monitor that uses a cuff around your upper arm, is used for these 
measurements.
Blood sampling
For Treatments A and B, it will be necessary to collect 2 samples of your blood during study day 1 and 6 samples 
during study day 2 (a total of 6 tablespoons per treatment and 12 tablespoons for the complete protocol) for 
measurement of the hormones that control blood pressure.  We will also measure sodium in your blood when you 
complete the pre-study 24hr-urine collection and the 2 4hr-urine collections. At some times, we will also measure 
carbidopa in your blood. To avoid sticking you repeatedly, we will place a small plastic tube (catheter) in your arm 
vein.  The samples will be 2-3 teaspoons each. 
Drug testing
In the evening prior to study day 1, you will be admitted to the Vanderbilt Clinical Research Center. In the morning, 
a small tube (catheter) will be placed in your arm vein in order to draw blood.   Baseline blood pressure and heart 
rate readings will be obtained and blood samples will be collected in the supine (lying on your back) and upright 
positions. You will void to finish the pre-study 24hr urine collection.  You will then be given a pill, either the active 
drug or the sugar pill. Whether you receive the active pill or the sugar pill as Treatment A will be decided by a 
procedure similar to tossing a coin. You will receive the other kind of pill as Treatment B. The medication will be 
given by mouth, every 6 hours, for 5 doses.  You will remain on the CRC during the day and we will measure your 
blood pressure and pulse after each dose, including overnight. You will need to consume the study diet for each 
meal, collect all urine, and take your study medication on schedule.  In the next morning, study day 2, blood 
pressure and heart rate readings will be obtained in the supine and upright positions. You will void to finish the 
study day 1 urine collection.  After taking the last dose of Treatment A, your supine blood pressure and heart rate 
will be measured every hour for 4 hours and again at 8 hours after treatment.  You will be able to sit up and move 
around during the study but you must lie supine for at least 30 minutes before each of the measurements.  
Standing vital signs will also be taken 2 hours after treatment.  A sample of blood will be collected at every 
scheduled blood pressure measurement after the 5th dose of study drug. Urine will also be collected from 0-4
hours, 4-8 hours and 8-24 hours.  If you live close enough to Vanderbilt, you may be discharged 8 hours after the 
last dose.
After at least another 24 hours, you will start collecting the pre-study urine for Treatment B. You may wait longer 
than 24 hours but you will need to eat the study diet for at least 3 days before study day 1 for Treatment B.  
Treatment B will follow the same schedule as Treatment A.
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RDCRN ARD #6101
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Table 1. Study Day Description
Day
Treatment
Timea
Pregnancy Test
Study Diet
Admit to CRC
Carbidopa or 
Placebo
Blood Draw
HR/BP
Urine
-3, -2
X
Start study diet
-1
0700
X
X
Start 24hr urine #1
1600
X
1
0645
X
X
X
End & restart 24hr urine
A
0700, 1300, 1900
X
Doses 1, 
2, 3
Continue 24hr urine #2
0900, 1500, 2100
X
X
Continue 24hr urine #2
2
0100
X
Dose 4
Continue 24hr urine #2
0300
X
X
Continue 24hr urine #2
0645-0700
X
Dose 5
X
End 24hr, start 4hr urine #1
0800, 0900, 1000
X
X
X
Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr urine 
#2
May be 
discharged
1500
X
X
X
End 4hr urine #2 & start 16hr urine
3(washout 
day)
0700
X
End 16hr urine
Repeat with Treatment B after at least 1 day
a these times are approximate
3. Costs to you if you take part in this study:
There will be no costs to you for any procedures done strictly for research.  All of the procedures described in this
consent form will be done for research.
4.
Side effects and risks that you can expect if you take part in this study:
Stopping medications might worsen your symptoms.  
Consuming a sodium- and caffeine-controlled diet that needs to be picked up at the CRC might be inconvenient.  
The diet might not be to your liking.  If you drink caffeinated beverages regularly 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.
Being woken up during the night might be an inconvenience for you.
Frequent blood pressure measurements with the cuff around your arm may produce some discomfort and 
occasional bruising of the upper arm.
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5
X


RDCRN ARD #6101
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Protocol Version: 25 March 2013
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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.  
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.
The study days might seem tedious and boring because they require you to lie down for an extended period of 
time before your blood pressure is monitored.  
Carbidopa – When any medication is used in testing, there is a small risk of an unforeseeable life-threatening 
allergic reaction.  Side effects of Carbidopa have only been reported when it is given with the drug levodopa for 
Parkinson’s disease at lower dosages than are being evaluated in this study.  Common adverse events with the 
carbidopa-levodopa combination include abnormal body movements and nausea.  Less common adverse effects 
are allergies, psychotic episodes (periods of confused thinking which can include hearing voices, seeing things that 
are not real, believing things that are not true and/or strange behavior), depression and dementia (loss of mental 
ability severe enough to cause problems with normal activities of daily living).  The dose you will receive in this 
study is a much higher dose than used in clinical practice, and there may be additional side effects that are not 
known at this time.  This medication has never been used at this dose or frequency.
5.
Risks that are not known:
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 breastfeed 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 while in this study:
If you are injured because you are in this study, you can get reasonable, immediate, and necessary medical care 
for your injury at Vanderbilt without charge to you. There are no plans for Vanderbilt to pay for the costs of care 
beyond your injury, or to give you money for such injury. There is no program for compensation through the 
National Institute of Neurological Disorders and Stroke (NINDS)/National Institutes of Health (NIH).
7.
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study are: a better understanding of the 
relationship between the plasma and urinary chemicals that we will measure and sodium excretion.  
The benefits you might get from being in this study are: this study might provide insight into the effectiveness of a 
potential treatment for your disorder and provide either direct or indirect benefit to your medical care.
8.
Other treatments you could get if you decide not to be in this study:
You may choose not to participate in this study.  
9.
Payments for your time spent taking part in this study or expenses:
You will not be paid for taking part 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.
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RDCRN ARD #6101
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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. We will cease to collect study 
information at the time of withdrawal of consent.  
12. Who to call for any questions or in case you are injured:
If you should have any questions about this research study or if you feel you have been hurt by being a part of this 
study, please feel free to contact  Emily Garland, Ph.D. at
or 
David Robertson, M.D. at 
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:  
All efforts, within reason, will be made to keep your personal information in your research record confidential but 
total confidentiality cannot be guaranteed. Research records will be stored in a locked office.  Digital records will be 
stored on password protected computers/servers.  Digital data files will be coded so that the participant’s name is 
not in the filename or other such identifiers. Every effort will be made to publish and present the data from this 
study.  At no time will any participant be identified in any such publication.  
14. Privacy:
All efforts, within reason, will be made to keep your protected health information (PHI) private. PHI is your health 
information that is, or has been gathered or kept by Vanderbilt as a result of your healthcare. This includes data 
gathered for research studies that can be traced back to you.  Using or sharing (“disclosure”) such data must follow 
federal privacy rules. By signing the consent for this study, you are agreeing (“authorization”) to the uses and likely
sharing of your PHI.  If you decide to be in this research study, you are also agreeing to let the study team use and 
share your PHI as described below.  
As part of the study, Dr. Garland and her co-investigators may report the results of your study and/or non-study 
related laboratory tests and electrocardiograms as well as parts of your medical record, to other members of the
research team and to 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, or the Vanderbilt University Institutional Review Board. Federal privacy rules may not 
apply to these groups; they have their own rules and codes to assure that all efforts, within reason, will be made to 
keep your PHI private. 
The study results will be kept in your research record for at least seven years after the study is finished.  At that 
time, the research data that has not been put in your medical record will be maintained in your research file for an 
unknown length of time. Any research data that has been put into your medical record will be kept for an unknown 
length of time.
The clinical information collected for this study will be stored at the Data Management and Coordinating Center at 
the 
. The data management center uses several layers of protection for the 
clinical data stored there. It meets all of the local and federal security requirements for research datacenters. Your 
information is stored only using a study ID.
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, we ask that 
you contact Dr. Emily Garland in writing and let her know that you withdraw your consent.  Her mailing address is 
Vanderbilt University
Nashville, TN 
At that time, we will stop getting any more data about you.  The health data we stored before you withdrew your 
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
34
consent may still be used for reporting and research quality.
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 BE IN THIS STUDY
I have read this consent form and the research study has been explained to me verbally.  All my questions 
have been answered, and I freely and voluntarily choose to take part in this study.   
                             
Date
Signature of patient/volunteer
Consent obtained by:  
 
 
                                        
       
Date
Signature
                                     
Printed Name and Title  


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APPENDIX 1b: Sample Informed Consent Form for Main Study – Healthy Volunteer
This informed consent applies to Healthy Volunteers
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 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.    
1.
What is the purpose of this study? 
You are being asked to take part in this research study because you are a healthy volunteer.  Data obtained from 
healthy persons will be compared with data from participants who have a condition called postural tachycardia 
syndrome.  A chemical in the kidney called dopamine plays an important role in maintaining your body’s salt levels.  
We will give you a drug called carbidopa that interferes with the formation of dopamine in the kidney, and we will 
measure how much salt is then excreted in your urine.  This drug has been used for many years at lower doses to 
treat Parkinson’s disease.  We will also measure your blood pressure and heart rate and some chemicals in your 
blood and urine that control them.  We will compare the effects of this drug to those of a sugar pill.  You will take the 
drug and the sugar pill on two different days (Treatment A and Treatment B), but you will not be told which one you 
are taking on a given day. We plan to enroll 16 participants with POTS and 16 healthy volunteers.      
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).  You will be asked some questions 
to ensure that you are in good health.  One of the investigators will explain the study to you and ask you to sign this 
consent form.  A copy of the consent form will be given to you.  Your participation is voluntary.
A minimum of 9 days will be required to complete this study.  You will need to spend 4 nights on the CRC, 2 nights 
for the active drug and 2 nights for the sugar pill.  On the morning after the first overnight, study day 1, we will 
collect pre-treatment data and then give you your first pill. You will take pills every 6 hours. You will need to be on 
the CRC so that we can measure your heart rate and blood pressure two hours after every dose. Studies on the 
second study day will last until about 3pm.   Different parts of the study are described below.
Drug withdrawal
You must remain off any medications that could affect blood pressure, the composition of your urine, or the 
chemicals that we will measure for three days prior to the first treatment and during the entire study.  This includes 
not only your usual scheduled medications, but also other drugs that might be taken intermittently.  
Pregnancy test
If you are a female, we will perform a pregnancy test on a sample of your blood when you are admitted to the 
hospital for this study.  Pregnant females may not participate in this research study.  
Diet
We will ask you to eat a standard diet with no caffeine and a controlled amount of salt for three days prior to each 
study day and during the study days.  We will provide this food to you and ask you to eat all of it and no other food.  
We will check to be sure that you are doing this by having you collect all of your urine for 24 hours and measuring 
the amount of salt in it (see below).
Urine Collection
You will collect your urine for 24 hours before administration of the first pill (active drug or sugar pill) and for the 
next 24 hours (study day 1).  After the last pill, on the second study day, you will collect samples over the first 4 
hours, from 4-8 hours, and from 8-24 hours.  The urine will be analyzed for sodium, potassium and for hormones 
that control blood pressure and heart rate.
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
36
Vital signs
Vital signs (blood pressure and heart rate) will be measured several times while you are lying down just before and 
after the treatment.  Sometimes you will be asked to stand quietly for 10 minutes for additional measurements.  A 
Dinamap, an automated blood pressure monitor that uses a cuff around your upper arm, is used for these 
measurements.
Blood sampling
For Treatments A and B, it will be necessary to collect 2 samples of your blood during study day 1 and 6 samples 
during study day 2 (a total of 6 tablespoons per treatment and 12 tablespoons for the complete protocol) for 
measurement of the hormones that control blood pressure.  We will also measure sodium in your blood when you 
complete the pre-study 24hr-urine collection and the 2 4hr-urine collections. At some times, we will also measure 
carbidopa in your blood. To avoid sticking you repeatedly, we will place a small plastic tube (catheter) in your arm 
vein.  The samples will be 2-3 teaspoons each. 
Drug testing
In the evening prior to study day 1, you will be admitted to the Vanderbilt Clinical Research Center. In the morning, 
a small tube (catheter) will be placed in your arm vein in order to draw blood.   Baseline blood pressure and heart 
rate readings will be obtained and blood samples will be collected in the supine (lying on your back) and upright 
positions. You will void to finish the pre-study 24hr urine collection.  You will then be given a pill, either the active 
drug or the sugar pill. Whether you receive the active pill or the sugar pill as Treatment A will be decided by a 
procedure similar to tossing a coin. You will receive the other kind of pill as Treatment B. The medication will be 
given by mouth, every 6 hours, for 5 doses.  You will remain on the CRC during the day and we will measure your 
blood pressure and pulse after each dose, including overnight. You will need to consume the study diet for each 
meal, collect all urine, and take your study medication on schedule.  In the next morning, study day 2, blood 
pressure and heart rate readings will be obtained in the supine and upright positions. You will void to finish the 
study day 1 urine collection.  After taking the last dose of Treatment A, your supine blood pressure and heart rate 
will be measured every hour for 4 hours and again at 8 hours after treatment.  You will be able to sit up and move 
around during the study but you must lie supine for at least 30 minutes before each of the measurements.  
Standing vital signs will also be taken 2 hours after treatment.  A sample of blood will be collected at every 
scheduled blood pressure measurement after the 5th dose of treatment.  Urine will also be collected from 0-4 hours, 
4-8 hours and 8-24 hours.  You may be discharged 8 hours after the last dose.
After at least another 24 hours, you will start collecting the pre-study urine for Treatment B. You may wait longer 
than 24 hours but you will need to eat the study diet for at least 3 days before study day 1 for Treatment B.  
Treatment B will follow the same schedule as Treatment A.
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
37
Table 1. Study Day Description
Day
Treatment
Timea
Pregnancy Test
Study Diet
Admit to CRC
Carbidopa or 
Placebo
Blood Draw
HR/BP
Urine
-3, -2
X
Start study diet
-1
0700
X
X
Start 24hr urine #1
1600
X
1
0645
X
X
X
End & restart 24hr urine
A
0700, 1300, 1900
X
Doses 1, 
2, 3
Continue 24hr urine #2
0900, 1500, 2100
X
X
Continue 24hr urine #2
2
0100
X
Dose 4
Continue 24hr urine #2
0300
X
X
Continue 24hr urine #2
0645-0700
X
Dose 5
X
End 24hr, start 4hr urine #1
0800, 0900, 1000
X
X
X
Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr urine 
#2
May be 
discharged
1500
X
X
X
End 4hr urine #2 & start 16hr urine
3(washout 
day)
0700
X
End 16hr urine
Repeat with Treatment B after at least 1 day
a these times are approximate
3.
Costs to you if you take part in this study:
There will be no costs to you for any procedures done strictly for research.  All of the procedures described in this 
consent form will be done for research.
4.
Side effects and risks that you can expect if you take part in this study:
Stopping medications might worsen your symptoms.  If you routinely take medications that can affect blood 
pressure or plasma volume, you will not be enrolled in the study.
Consuming a sodium- and caffeine-controlled diet that needs to be picked up at the CRC might be inconvenient.  
The diet might not be to your liking.  If you drink caffeinated beverages regularly 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.
Being woken up during the night might be an inconvenience for you.
Frequent blood pressure measurements with the cuff around your arm may produce some discomfort and 
occasional bruising of the upper arm.
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Continu
Co
C
X
5
X


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
38
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
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.
The study days might seem tedious and boring because they require you to lie down for an extended period of 
time before your blood pressure is monitored.  
Carbidopa – When any medication is used in testing, there is a small risk of an unforeseeable life-threatening 
allergic reaction.  Side effects of Carbidopa have only been reported when it is given with the drug levodopa for 
Parkinson’s disease at lower dosages than are being evaluated in this study.  Common adverse events with the 
carbidopa-levodopa combination include abnormal body movements and nausea.  Less common adverse effects 
are allergies, psychotic episodes (periods of confused thinking which can include hearing voices, seeing things that 
are not real, believing things that are not true and/or strange behavior), depression and dementia (loss of mental 
ability severe enough to cause problems with normal activities of daily living).  The dose you will receive in this 
study is a much higher dose than used in clinical practice, and there may be additional side effects that are not 
known at this time.  This medication has never been used at this dose or frequency.
5.
Risks that are not known:
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 breastfeed 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 while in this study:
If you are injured because you are in this study, you can get reasonable, immediate, and necessary medical care 
for your injury at Vanderbilt without charge to you. There are no plans for Vanderbilt to pay for the costs of care 
beyond your injury, or to give you money for such injury. There is no program for compensation through the 
National Institute of Neurological Disorders and Stroke (NINDS)/National Institutes of Health (NIH).
7.
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study are: a better understanding of the 
relationship between the plasma and urinary chemicals that we will measure and sodium excretion. The benefits 
you might get from being in this study are: none anticipated.
8.
Other treatments you could get if you decide not to be in this study:
You may choose not to participate in this study.  
9.
Payments for your time spent taking part in this study or expenses:
$200 for completing Treatment A and an additional $200 for completing Treatment B.
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.
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
39
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. We will cease to collect study 
information at the time of withdrawal of consent.  
12. Who to call for any questions or in case you are injured:
If you should have any questions about this research study or if you feel you have been hurt by being a part of this 
study, please feel free to contact  Emily Garland, Ph.D. at 
or 
David Robertson, M.D. at 
.
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:  
All efforts, within reason, will be made to keep your personal information in your research record confidential but 
total confidentiality cannot be guaranteed. Research records will be stored in a locked office.  Digital records will be 
stored on password protected computers/servers.  Digital data files will be coded so that the participant’s name is 
not in the filename or other such identifiers. Every effort will be made to publish and present the data from this 
study.  At no time will any participant be identified in any such publication.  
14. Privacy:
All efforts, within reason, will be made to keep your protected health information (PHI) private. PHI is your health 
information that is, or has been gathered or kept by Vanderbilt as a result of your healthcare.  This includes data 
gathered for research studies that can be traced back to you.  Using or sharing (“disclosure”) such data must follow 
federal privacy rules. By signing the consent for this study, you are agreeing (“authorization”) to the uses and likely 
sharing of your PHI.  If you decide to be in this research study, you are also agreeing to let the study team use and 
share your PHI as described below.
As part of the study, Dr. Garland and her co-investigators may report the results of your study and/or non-study 
related laboratory tests and electrocardiograms as well as parts of your medical record, to other members of the
research team and to 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, or the Vanderbilt University Institutional Review Board. Federal privacy rules may not 
apply to these groups; they have their own rules and codes to assure that all efforts, within reason, will be made to 
keep your PHI private. 
The study results will be kept in your research record for at least seven years after the study is finished.  At that 
time, the research data that has not been put in your medical record will be maintained in your research file for an 
unknown length of time. Any research data that has been put into your medical record will be kept for an unknown 
length of time.
The clinical information collected for this study will be stored at the Data Management and Coordinating Center at 
the 
 The data management center uses several layers of protection for the 
clinical data stored there. It meets all of the local and federal security requirements for research datacenters. Your 
information is stored only using a study ID.
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, we ask that 
you contact Dr. Emily Garland in writing and let her know that you withdraw your consent.  Her mailing address is 
Vanderbilt University
Nashville, TN 
At that time, we will stop getting any more data about you.  The health data we stored before you withdrew your 
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
40
consent may still be used for reporting and research quality.
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 BE IN THIS STUDY
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.   
                                     
Date
Signature of patient/volunteer
Consent obtained by:  
 
 
                                    
Date
Signature
                                       
Printed Name and Title  


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
41
APPENDIX 1c: Sample Informed Consent Form for Dose Escalation Study–  POTS
This informed consent applies to Participants with POTS
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 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.    
1.
What is the purpose of this study? 
You are being asked to take part in this research study because you have Postural Tachycardia Syndrome (POTS)
Data obtained from healthy persons will be compared with data from participants who have POTS.  A chemical in 
the kidney called dopamine plays an important role in maintaining your body’s salt levels.  We will give you a drug 
called carbidopa that interferes with the formation of dopamine in the kidney, and we will measure how much salt is 
then excreted in your urine.  This drug has been used for many years at lower doses to treat Parkinson’s disease.  
We will also measure your blood pressure and heart rate and some chemicals in your blood and urine that control 
them.  We will compare the effects of this drug to those of a sugar pill.  You will take the drug and the sugar pill on 
two different days (Treatment A and Treatment B), but you will not be told which one you are taking on a given day.
Because we do not know what the best dose of carbidopa is, we are first doing this study to compare the effects of 
different doses. You will take 50 mg, 100 mg or 200 mg of carbidopa every 6 hours for 5 doses. We will monitor you 
for the effects we are studying and for any problems. Only if no problems occur after the 50 mg dose, we will enroll 
two more people at 100 mg, then 200 mg.  This is called “dose escalation”.  Although we do not expect the doses of 
carbidopa to cause any problems, we are doing this study to make sure that participants do not have any problems 
at each dose level before we enroll at a higher dose.  
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).  You will be asked some questions 
about your health other than POTS.  One of the investigators will explain the study to you and ask you to sign this 
consent form.  A copy of the consent form will be given to you.  Your participation is voluntary.
A minimum of 9 days will be required to complete this study.  You will need to spend 4 nights on the CRC, 2 nights 
for the active drug and 2 nights for the sugar pill.  On the morning after the first overnight, study day 1, we will 
collect pre-treatment data and then give you your first pill. You will take pills every 6 hours. You will need to stay on 
the CRC during the day so that we can monitor your blood pressure and pulse and make sure that there are no 
health problems associated with the dose of carbidopa that you take. Studies on the second study day will last until 
about 3pm.   Different parts of the study are described below.
Drug withdrawal
You must remain off any medications that could affect blood pressure, the composition of your urine, or the 
chemicals that we will measure for three days prior to the first treatment and during the entire study.  This includes 
not only your usual scheduled medications, but also other drugs that might be taken intermittently.  You should 
consult your primary care physician before stopping any drug and contact the Principal Investigator or his nurse if 
any problems occur prior to admission. Your symptoms, such as dizziness, fatigue, nausea, fainting or near 
fainting, might get worse, but they should be relieved by lying down.  If necessary, we will admit you to the hospital 
and take you off your medications there.  While you are an inpatient on the CRC, we will check your general 
condition, blood pressure and heart rate regularly to reduce any risk. 
Pregnancy test
If you are a female, we will perform a pregnancy test on a sample of your blood when you are admitted to the 
hospital for this study.  Pregnant females may not participate in this research study.  
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
42
Diet
We will ask you to eat a standard diet with no caffeine and a controlled amount of salt for three days prior to each 
study day and during the study days.  We will provide this food to you and ask you to eat all of it and no other food.  
We will check to be sure that you are doing this by having you collect all of your urine for 24 hours and measuring 
the amount of salt in it (see below).
Urine Collection
You will collect your urine for 24 hours before administration of the first pill (active drug or sugar pill) and for the 
next 24 hours (study day 1).  After the last pill, on the second study day, you will collect samples over the first 4 
hours, from 4-8 hours, and from 8-24 hours.  The urine will be analyzed for sodium, potassium and for hormones 
that control blood pressure and heart rate.
Vital signs
Vital signs (blood pressure and heart rate) will be measured several times while you are lying down just before and 
following the last dose of the treatment.  As part of the dose escalation evaluation, we will also measure your blood 
pressure and heart rate 2 hours after every dose while you are lying down, including overnight. Sometimes you will 
be asked to stand quietly for 10 minutes for additional measurements.  A Dinamap, an automated blood pressure 
monitor that uses a cuff around your upper arm, is used for these measurements. An electrocardiogram (EKG) will 
be obtained before the first dose and after the 5th dose of Treatments A and B. 
Blood sampling
For Treatments A and B, as part of the safety evaluation, 2 teaspoons of blood will be collected before the 1st dose 
and after the 5th dose of drug, in addition to smaller samples to be collected after every dose, including overnight. A 
total of 5 teaspoons of blood will be needed for the safety evaluation part of the study. It will also be necessary to 
collect 2 samples of your blood during study day 1 and 6 samples during study day 2 for measurement of the 
hormones that control blood pressure.  We will also measure sodium in your blood when you complete the pre-
study 24hr- urine collections and the 2 4hr-urine collections. At some times, we will also measure carbidopa in your 
blood. The study samples will be 2-3 teaspoons each. To avoid sticking you repeatedly, we will place a small plastic 
tube (catheter) in your arm vein.  The total amount for the entire study with Treatments A and B will be about 16 
tablespoons. 
Drug testing
In the evening prior to study day 1, you will be admitted to the Vanderbilt Clinical Research Center. In the morning, 
a small tube (catheter) will be placed in your arm vein in order to draw blood.   Baseline blood pressure and heart 
rate readings will be obtained and blood samples will be collected in the supine (lying on your back) and upright 
positions. You will void to finish the pre-study 24hr urine collection.  You will then be given a pill, either the active 
drug or the sugar pill. Whether you receive the active pill or the sugar pill as Treatment A will be decided by a 
procedure similar to tossing a coin. You will receive the other kind of pill as Treatment B. The medication will be 
given by mouth, every 6 hours, for 5 doses. You will stay on the CRC for monitoring throughout day 1. In addition 
to the vital signs and the blood draws described above, at two hours after every dose, you will be questioned about 
any symptoms or unusual feelings you may be experiencing. We will need to wake you up around 3am for these 
measurements. In the next morning, study day 2, blood pressure and heart rate readings will be obtained in the 
supine and upright positions. You will void to finish the study day 1 urine collection.  After taking the last dose of 
Treatment A, your supine blood pressure and heart rate will be measured every hour for 4 hours and again at 8 
hours after treatment.  You will be able to sit up and move around during the study but you must lie supine for at 
least 30 minutes before each of the measurements.  Standing vital signs will also be taken 2 hours after treatment.  
A sample of blood will be collected at every scheduled blood pressure measurement after the 5th dose of treatment.
Urine will also be collected from 0-4 hours, 4-8 hours and 8-24 hours.  If you live close enough to Vanderbilt, you 
may be discharged 8 hours after the last dose.
After at least another 24 hours, you will start collecting the pre-study urine for Treatment B. You may wait longer 
than 24 hours but you will need to eat the study diet for at least 3 days before study day 1 for Treatment B.  
Treatment B will follow the same schedule as Treatment A.
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
43
Table 1. Study Day Description
Day
Treatment
Timea
Assessments for 
Tolerability
Pregnancy Test
Admit to CRC
Study Diet
Carbidopa or 
Placebo
Blood Draw
HR/BP
Urine
Pre-study
X
-3, -2
X
Start study diet
-1
0700
X
Start 24hr urine #1
1600
X
1
0645b 
X
X
X
End & restart 24hr urine
A 0700, 1300, 1900
X
Doses 1, 
2, 3
Continue 24hr urine #2
0900, 1500, 2100
X
X
X
X
Continue 24hr urine #2
2
0100
X
Dose 4
Continue 24hr urine #2
0300
X
X
X
X
Continue 24hr urine #2
0645-0700
X
Dose 5
X
End 24hr, start 4hr urine #1
0800
X
X
X
Continue 4hr urine #1
0900
X
X
X
X
Continue 4hr urine #1
1000
X
X
X
Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr urine 
#2
May be 
discharged
1500
X
X
X
End 4hr urine #2 & start 16hr urine
3(washout 
day)
0700
X
End 16hr urine
Repeat with Treatment B after at least 1 day
a times are approximate
b Blood pressure and heart rate will be measured and a blood sample will be collected before the first dose and at 2 
hours after each dose as part of the safety evaluation. 
3.
Costs to you if you take part in this study:
There will be no costs to you for any procedures done strictly for research.  All of the procedures described in this 
consent form will be done for research.
4.
Side effects and risks that you can expect if you take part in this study:
Stopping medications might worsen your symptoms.  If you routinely take medications that can affect blood 
pressure or plasma volume, you will not be enrolled in the study.
Consuming a sodium- and caffeine-controlled diet that needs to be picked up at the CRC might be inconvenient.  
The diet might not be to your liking.  If you drink caffeinated beverages regularly 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.
art rate wi
art rate w
part of
part of
X
X
X
Rep
R
& restar
& restar
Continue
Continue
X
Cont
Cont
X
X
ose 5
ose 5


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
44
Staying in the hospital might be an inconvenience for you.
Being woken up during the night might be an inconvenience for you.
Frequent blood pressure measurements with the cuff around your arm 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
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.
The study days might seem tedious and boring because they require you to lie down for an extended period of 
time before your blood pressure is monitored.  
Carbidopa – When any medication is used in testing, there is a small risk of an unforeseeable life-threatening 
allergic reaction.  Side effects of Carbidopa have only been reported when it is given with the drug levodopa for 
Parkinson’s disease at lower dosages than are being evaluated in this study.  Common adverse events with the 
carbidopa-levodopa combination include abnormal body movements and nausea.  Less common adverse effects 
are allergies, psychotic episodes (periods of confused thinking which can include hearing voices, seeing things that 
are not real, believing things that are not true and/or strange behavior), depression and dementia (loss of mental 
ability severe enough to cause problems with normal activities of daily living).  The dose you will receive in this 
study will be between 50 mg – 200 mg.  There may be additional side effects that are not known at this time.  This 
medication has never been used at the highest dose or frequency.
5.
Risks that are not known:
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 breastfeed 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 while in this study:
If you are injured because you are in this study, you can get reasonable, immediate, and necessary medical care 
for your injury at Vanderbilt without charge to you. There are no plans for Vanderbilt to pay for the costs of care 
beyond your injury, or to give you money for such injury. There is no program for compensation through the 
National Institute of Neurological Disorders and Stroke (NINDS)/National Institutes of Health (NIH).
7.
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study are: a better understanding of the 
relationship between the plasma and urinary chemicals that we will measure and sodium excretion. The benefits 
you might get from being in this study are: none anticipated.
8.
Other treatments you could get if you decide not to be in this study:
You may choose not to participate in this study.  
9.
Payments for your time spent taking part in this study or expenses:
otent
ten
you are i
you are
you 
yo
ctiv
cti
e additio
dditio
e or frequenc
r freque
ul to an unbo
o an un
l participants
articipa
ther a child w
ther a child 
ed while in 
 while in
al will h
l w
e down for 
own for 
l risk of a
risk of 
d when it 
when it 
n this study
n this stud
ments and 
ments and 
g which can
hich can
ge behavio
e behav
ties of 
ies o


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
45
You will not be paid for taking part 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.
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. We will cease to collect study 
information at the time of withdrawal of consent.  
12. Who to call for any questions or in case you are injured:
If you should have any questions about this research study or if you feel you have been hurt by being a part of this 
study, please feel free to contact  Emily Garland, Ph.D. at 
or 
David Robertson, M.D. at 
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:  
All efforts, within reason, will be made to keep your personal information in your research record confidential but 
total confidentiality cannot be guaranteed. Research records will be stored in a locked office.  Digital records will be 
stored on password protected computers/servers.  Digital data files will be coded so that the participant’s name is 
not in the filename or other such identifiers. Every effort will be made to publish and present the data from this 
study.  At no time will any participant be identified in any such publication.  
14. Privacy:
All efforts, within reason, will be made to keep your protected health information (PHI) private. PHI is your health 
information that is, or has been gathered or kept by Vanderbilt as a result of your healthcare.  This includes data 
gathered for research studies that can be traced back to you.  Using or sharing (“disclosure”) such data must follow 
federal privacy rules. By signing the consent for this study, you are agreeing (“authorization”) to the uses and likely 
sharing of your PHI.  If you decide to be in this research study, you are also agreeing to let the study team use and 
share your PHI as described below.
As part of the study, Dr. Garland and her co-investigators may report the results of your study and/or non-study 
related laboratory tests and electrocardiograms as well as parts of your medical record, to other members of the
research team and to 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, or the Vanderbilt University Institutional Review Board. Federal privacy rules may not 
apply to these groups; they have their own rules and codes to assure that all efforts, within reason, will be made to 
keep your PHI private. 
The study results will be kept in your research record for at least seven years after the study is finished.  At that 
time, the research data that has not been put in your medical record will be maintained in your research file for an 
unknown length of time. Any research data that has been put into your medical record will be kept for an unknown 
length of time.
The clinical information collected for this study will be stored at the Data Management and Coordinating Center at 
the 
. The data management center uses several layers of protection for the 
ide to
e t
below.
below.
Garland a
Garland 
d ele
d e
da
d
rt will be 
will be
any such pu
ny such 
keep your pro
ep your 
ed or kept by
or kept
an be traced 
an be traced
e consent fo
consent 
be in t
be
en 
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5) 322
32 -291
29
nformation 
rmation 
 will be sto
will be st
a files 
a files


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
46
clinical data stored there. It meets all of the local and federal security requirements for research datacenters. Your 
information is stored only using a study ID.
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, we ask that 
you contact Dr. Emily Garland in writing and let her know that you withdraw your consent.  Her mailing address is 
 
Vanderbilt University
Nashville, TN 
At that time, we will stop getting any more data about you.  The health data we stored before you withdrew your 
consent may still be used for reporting and research quality.
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 BE IN THIS STUDY
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.   
                                  
Date 
   Signature of patient/volunteer     
Consent obtained by:  
 
 
                              
Date 
   Signature   
                                      
Printed Name and Title  
ined
ined
o take pa
take pa


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
47
APPENDIX 1d: Sample Informed Consent Form for Dose Escalation Study –  Healthy 
Volunteers 
This informed consent applies to Healthy Volunteers 
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 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.    
1.
What is the purpose of this study? 
You are being asked to take part in this research study because you are a healthy volunteer.  Data obtained from 
healthy persons will be compared with data from participants who have POTS.  A chemical in the kidney called 
dopamine plays an important role in maintaining your body’s salt levels.  We will give you a drug called carbidopa 
that interferes with the formation of dopamine in the kidney, and we will measure how much salt is then excreted in 
your urine.  This drug has been used for many years at lower doses to treat Parkinson’s disease.  We will also 
measure your blood pressure and heart rate and some chemicals in your blood and urine that control them.  We will 
compare the effects of this drug to those of a sugar pill.  You will take the drug and the sugar pill on two different 
days (Treatment A and Treatment B), but you will not be told which one you are taking on a given day. Because 
we do not know what the best dose of carbidopa is, we are first doing this study to compare the effects of different 
doses. You will take 50 mg, 100 mg or 200 mg of carbidopa every 6 hours for 5 doses. We will monitor you for the 
effects we are studying and for any problems. Only if no problems occur after the 50 mg dose, we will enroll two 
more people at 100 mg, then 200 mg.  This is called “dose escalation”.  Although we do not expect the doses of 
carbidopa to cause any problems, we are doing this study to make sure that participants do not have any problems 
at each dose level before we enroll at a higher dose.     
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).  You will be asked some questions 
to ensure that you are in good health.  One of the investigators will explain the study to you and ask you to sign this 
consent form.  A copy of the consent form will be given to you.  Your participation is voluntary.
A minimum of 9 days will be required to complete this study.  You will need to spend 4 nights on the CRC, 2 nights 
for the active drug and 2 nights for the sugar pill.  On the morning after the first overnight, study day 1, we will 
collect pre-treatment data and then give you your first pill. You will take pills every 6 hours. You will need to stay on 
the CRC during the day so that we can monitor your blood pressure and pulse and make sure that there are no 
health problems associated with the dose of carbidopa that you take. Studies on the second study day will last until 
about 3pm.   Different parts of the study are described below.
Drug withdrawal
You must remain off any medications that could affect blood pressure, the composition of your urine, or the 
chemicals that we will measure for three days prior to the first treatment and during the entire study.  This includes 
not only your usual scheduled medications, but also other drugs that might be taken intermittently.  
Pregnancy test
If you are a female, we will perform a pregnancy test on a sample of your blood when you are admitted to the 
hospital for this study.  Pregnant females may not participate in this research study.  
Diet
We will ask you to eat a standard diet with no caffeine and a controlled amount of salt for three days prior to each 
study day and during the study days.  We will provide this food to you and ask you to eat all of it and no other food.  
equired 
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ll you be in t
you be i
nderbilt Clinic
rbilt Cl
  One of the 
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t form wi
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chemical 
hemical
ll give you 
l give yo
sure how m
sure how
at Parkinso
t Parkinso
ur blood an
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h one you 
one you 
doing this 
oing this 
every 6 hou
every 6 ho
blems oc
lems 
alat
alat


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
48
We will check to be sure that you are doing this by having you collect all of your urine for 24 hours and measuring 
the amount of salt in it (see below).
Urine Collection
You will collect your urine for 24 hours before administration of the first pill (active drug or sugar pill) and for the 
next 24 hours (study day 1).  After the last pill, on the second study day, you will collect samples over the first 4 
hours, from 4-8 hours, and from 8-24 hours.  The urine will be analyzed for sodium, potassium and for hormones 
that control blood pressure and heart rate.
Vital signs
Vital signs (blood pressure and heart rate) will be measured several times while you are lying down just before and 
following the last dose of the treatment.  As part of the dose escalation evaluation, we will also measure your blood 
pressure and heart rate 2 hours after every dose while you are lying down, including overnight. Sometimes you will 
be asked to stand quietly for 10 minutes for additional measurements.  A Dinamap, an automated blood pressure 
monitor that uses a cuff around your upper arm, is used for these measurements. An electrocardiogram (EKG) will 
be obtained before the first dose and after the 5th dose of Treatments A and B. 
Blood sampling
For Treatments A and B, as part of the safety evaluation, 2 teaspoons of blood will be collected before the 1st dose 
and after the 5th dose of drug, in addition to smaller samples to be collected after every dose, including overnight. A 
total of 5 teaspoons of blood will be needed for the safety evaluation part of the study. It will also be necessary to 
collect 2 samples of your blood during study day 1 and 6 samples during study day 2 for measurement of the 
hormones that control blood pressure.  We will also measure sodium in your blood when you complete the pre-
study 24hr- urine collections and the 2 4hr-urine collections. At some times, we will also measure carbidopa in your 
blood. The study samples will be 2-3 teaspoons each. To avoid sticking you repeatedly, we will place a small plastic 
tube (catheter) in your arm vein.  The total amount for the entire study with Treatments A and B will be about 16 
tablespoons. 
Drug testing
In the evening prior to study day 1, you will be admitted to the Vanderbilt Clinical Research Center. In the morning, 
a small tube (catheter) will be placed in your arm vein in order to draw blood.   Baseline blood pressure and heart 
rate readings will be obtained and blood samples will be collected in the supine (lying on your back) and upright 
positions. You will void to finish the pre-study 24hr urine collection.  You will then be given a pill, either the active 
drug or the sugar pill. Whether you receive the active pill or the sugar pill as Treatment A will be decided by a 
procedure similar to tossing a coin. You will receive the other kind of pill as Treatment B. The medication will be 
given by mouth, every 6 hours, for 5 doses. You will stay on the CRC for monitoring throughout day 1. In addition 
to the vital signs and the blood draws described above, at two hours after every dose, you will be questioned about 
any symptoms or unusual feelings you may be experiencing. We will need to wake you up around 3am for these 
measurements. In the next morning, study day 2, blood pressure and heart rate readings will be obtained in the 
supine and upright positions. You will void to finish the study day 1 urine collection.  After taking the last dose of 
Treatment A, your supine blood pressure and heart rate will be measured every hour for 4 hours and again at 8 
hours after treatment.  You will be able to sit up and move around during the study but you must lie supine for at 
least 30 minutes before each of the measurements.  Standing vital signs will also be taken 2 hours after treatment.  
A sample of blood will be collected at every scheduled blood pressure measurement after the 5th dose of treatment.
Urine will also be collected from 0-4 hours, 4-8 hours and 8-24 hours.  You may be discharged 8 hours after the last 
dose.
After at least another 24 hours, you will start collecting the pre-study urine for Treatment B. You may wait longer 
than 24 hours but you will need to eat the study diet for at least 3 days before study day 1 for Treatment B.  
Treatment B will follow the same schedule as Treatment A.
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 receiv
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 times, we
times, we
cking you 
king you 
e study with
study with


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
49
Table 1. Study Day Description
Day
Treatment
Timea
Assessments for 
Tolerability
Pregnancy Test
Admit to CRC
Study Diet
Carbidopa or 
Placebo
Blood Draw
HR/BP
Urine
Pre-study
X
-3, -2
X
Start study diet
-1
0700
X
Start 24hr urine #1
1600
X
1
0645b 
X
X
X
End & restart 24hr urine
A 0700, 1300, 1900
X
Doses 1, 
2, 3
Continue 24hr urine #2
0900, 1500, 2100
X
X
X
X
Continue 24hr urine #2
2
0100
X
Dose 4
Continue 24hr urine #2
0300
X
X
X
X
Continue 24hr urine #2
0645-0700
X
Dose 5
X
End 24hr, start 4hr urine #1
0800
X
X
X
Continue 4hr urine #1
0900
X
X
X
X
Continue 4hr urine #1
1000
X
X
X
Continue 4hr urine #1
1100
X
X
X
End 4hr urine #1 & start 4hr urine 
#2
May be 
discharged
1500
X
X
X
End 4hr urine #2 & start 16hr urine
3(washout 
day)
0700
X
End 16hr urine
Repeat with Treatment B after at least 1 day
a times are approximate
b Blood pressure and heart rate will be measured and a blood sample will be collected before the first dose and at 2 
hours after each dose as part of the safety evaluation. 
3.
Costs to you if you take part in this study:
There will be no costs to you for any procedures done strictly for research.  All of the procedures described in this 
consent form will be done for research.
4.
Side effects and risks that you can expect if you take part in this study:
Stopping medications might worsen your symptoms.  If you routinely take medications that can affect blood 
pressure or plasma volume, you will not be enrolled in the study.
Consuming a sodium- and caffeine-controlled diet that needs to be picked up at the CRC might be inconvenient.  
The diet might not be to your liking.  If you drink caffeinated beverages regularly 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.
t rate will b
rate will b
s part of th
s part of t
X
X
Repeat
R
res
res
Continue 24
ntinue 24
X
Continu
Conti
Co
Co
X
X
5
X


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
50
Staying in the hospital might be an inconvenience for you.
Being woken up during the night might be an inconvenience for you.
Frequent blood pressure measurements with the cuff around your arm 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
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.
The study days might seem tedious and boring because they require you to lie down for an extended period of 
time before your blood pressure is monitored.  
Carbidopa – When any medication is used in testing, there is a small risk of an unforeseeable life-threatening 
allergic reaction.  Side effects of Carbidopa have only been reported when it is given with the drug levodopa for 
Parkinson’s disease at lower dosages than are being evaluated in this study.  Common adverse events with the 
carbidopa-levodopa combination include abnormal body movements and nausea.  Less common adverse effects 
are allergies, psychotic episodes (periods of confused thinking which can include hearing voices, seeing things that 
are not real, believing things that are not true and/or strange behavior), depression and dementia (loss of mental 
ability severe enough to cause problems with normal activities of daily living).  The dose you will receive in this 
study will be between 50 mg – 200 mg.  There may be additional side effects that are not known at this time.  This 
medication has never been used at the highest dose or frequency.
5.
Risks that are not known:
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 breastfeed 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 while in this study:
If you are injured because you are in this study, you can get reasonable, immediate, and necessary medical care 
for your injury at Vanderbilt without charge to you. There are no plans for Vanderbilt to pay for the costs of care 
beyond your injury, or to give you money for such injury. There is no program for compensation through the 
National Institute of Neurological Disorders and Stroke (NINDS)/National Institutes of Health (NIH).
7.
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study are: a better understanding of the 
relationship between the plasma and urinary chemicals that we will measure and sodium excretion. The benefits 
you might get from being in this study are: none anticipated.
8.
Other treatments you could get if you decide not to be in this study:
You may choose not to participate in this study.  
9.
Payments for your time spent taking part in this study or expenses:
$225 for completing Treatment A and an additional $225 for completing Treatment B.
ou are inj
ou are in
se you are
se you are
t with
t w
add
dd
r frequen
eque
o an unborn 
an unb
articipants an
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a child 
d while in this
d while in th
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al will ha
re
own for a
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isk of an u
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his study.  
s study. 
nts and na
nts and na
hich can in
hich can i
behavior)
ehavior)
vities of da
ties of d
ional s
onal 


RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
51
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.
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. We will cease to collect study 
information at the time of withdrawal of consent.  
12. Who to call for any questions or in case you are injured:
If you should have any questions about this research study or if you feel you have been hurt by being a part of this 
study, please feel free to contact  Emily Garland, Ph.D. at 
or 
David Robertson, M.D. at 
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:  
All efforts, within reason, will be made to keep your personal information in your research record confidential but 
total confidentiality cannot be guaranteed. Research records will be stored in a locked office.  Digital records will be 
stored on password protected computers/servers.  Digital data files will be coded so’ that the participant’s name is 
not in the filename or other such identifiers. Every effort will be made to publish and present the data from this 
study.  At no time will any participant be identified in any such publication. 
14. Privacy:
All efforts, within reason, will be made to keep your protected health information (PHI) private. PHI is your health 
information that is, or has been gathered or kept by Vanderbilt as a result of your healthcare.  This includes data 
gathered for research studies that can be traced back to you.  Using or sharing (“disclosure”) such data must follow 
federal privacy rules. By signing the consent for this study, you are agreeing (“authorization”) to the uses and likely 
sharing of your PHI.  If you decide to be in this research study, you are also agreeing to let the study team use and 
share your PHI as described below.
As part of the study, Dr. Garland and her co-investigators may report the results of your study and/or non-study 
related laboratory tests and electrocardiograms as well as parts of your medical record, to other members of the
research team and to 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, or the Vanderbilt University Institutional Review Board. Federal privacy rules may not 
apply to these groups; they have their own rules and codes to assure that all efforts, within reason, will be made to 
keep your PHI private. 
The study results will be kept in your research record for at least seven years after the study is finished.  At that 
time, the research data that has not been put in your medical record will be maintained in your research file for an 
unknown length of time. Any research data that has been put into your medical record will be kept for an unknown 
length of time.
The clinical information collected for this study will be stored at the Data Management and Coordinating Center at 
the 
. The data management center uses several layers of protection for the 
clinical data stored there. It meets all of the local and federal security requirements for research datacenters. Your 
information is stored only using a study ID.
and and 
and and 
nd electroc
d electro
llaborator
llaborato
med
me
suc
su
your protecte
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RDCRN ARD #6101
Peripheral Dopamine in POTS
Protocol Version: 25 March 2013
52
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, we ask that 
you contact Dr. Emily Garland in writing and let her know that you withdraw your consent.  Her mailing address is 
Vanderbilt University
Nashville, TN 
At that time, we will stop getting any more data about you.  The health data we stored before you withdrew your 
consent may still be used for reporting and research quality.
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 BE IN THIS STUDY
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.   
                                 
Date
Signature of patient/volunteer
Consent obtained by:  
 
 
                             
Date 
   Signature   
                               
Printed Name and Title