Clinical trial NCT02784535
Conditions: Neurogenic Orthostatic Hypotension
Keywords: norepinephrine transporter inhibitors
Sponsor: Vanderbilt University Medical Center
Start date: 2016-08-29; Completion date: 2023-06-01
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Drug therapy for patients suffering from autonomic failure and neurogenic orthostatic hypotension are scarce and not effective. If left untreated, these patients have the highest risk of syncope, falls and fall-related injuries. The proposed study will determine the clinical benefit of a commercially available drug, atomoxetine, to reduce symptoms associated with neurogenic orthostatic hypotension in patients with autonomic failure.

Detailed description:
Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. These patients develop neurogenic orthostatic hypotension (OH) because of impaired autonomic reflexes that control cardiovascular and neuro-humoral adaptation to upright posture. The treatment of neurogenic OH is challenging; the therapeutic options are scarce, and some patients are refractory to treatment.

Atomoxetine is a selective norepinephrine transporter inhibitor that increases the availability of norepinephrine in the synapse by blocking its reuptake. Our preliminary data in sixty-five patients with primary autonomic failure and neurogenic OH showed that atomoxetine was more effective than midodrine, standard of care, in improving standing SBP (+7.5 mm Hg). Notably, only atomoxetine and not midodrine induced a significant reduction in OH-related symptoms (lightheadedness and dizziness) compared with placebo. In this proposal, we will test the hypothesis that prolonged administration of the norepinephrine transporter blocker, atomoxetine, improves OH-related symptoms and OH-impact on daily activities compared with placebo in autonomic failure patients. We propose a randomized, double-blind, placebo-controlled, 2x2 crossover study.

Arms: arm 1: placebo capsules arm 2: atomoxetine capsules 10 mg or 18 mg
Interventions: intervention 1: Atomoxetine intervention 2: Placebo
Intervention descriptions: intervention 1: norepinephrine transporter inhibitor intervention 2: placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
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04/22/2019 
 
 
 
Phase 2 Norepinephrine Transporter Blockade, Autonomic 
Failure IND117394 12/28/12 
 
Principal Investigators: 
 Cyndya A. Shibao, M.D. 
Assistant Professor of Medicine 
Vanderbilt Autonomic Dysfunction Center 
Vanderbilt University 
 
Chang Yu, PhD 
 
 
 
 
Associate Professor of Biostatistics 
Vanderbilt University  
 
 
Vanderbilt University Medical Center 
 
Co-PI: David Robertson, Professor of Medicine and Pharmacology, Clinical Pharmacology 
Italo Biaggioni, Professor of Medicine and Pharmacology, Clinical Pharmacology,  
James Muldowney, Assistant Professor of Medicine 
Amanda Peltier, Associate Professor of Medicine 
Andre Diedrich, Research Associate Professor of Medicine and Clinical Pharmacology 
Luis Okamoto, Research Instructor, Division of Clinical Pharmacology 
Jorge Celedonio, Research Fellow, Clinical Pharmacology 
Bonnie Black, Research Nurse 
 
 
 
 


 
 
 
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04/22/2019 
 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Specific Aims 
2.0 
Background 
3.0 
Preliminary Data 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Statistical Considerations 
8.0 
Risks of Investigational Agents/Devices (side effects) 
9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
10.0 Study Withdrawal/Discontinuation 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
13.0    Data-Coordinating Center 
Appendices 
Appendix A Study Procedure Calendar 


 
 
 
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1.0 
Specific Aims 
 
Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the 
autonomic nervous system. The presence and nature of the autonomic and neurological 
abnormalities depend on the location of the pathological lesion known as α-synuclein deposits. In 
multiple system atrophy (MSA), α-synuclein are found as glial cytoplasmic inclusions in basal 
ganglia or cerebellar structures causing impairment of central autonomic pathways crucial for 
autonomic cardiovascular control; the peripheral postganglionic sympathetic fibers are 
preserved.(1) In contrast, in pure autonomic failure (PAF) α-synuclein deposits are found in pre-
ganglionic, postganglionic sympathetic fibers as well as in autonomic ganglia; central autonomic 
pathways are spared.(2)  
Early in the course of the disease it is difficult to differentiate clinically between MSA and PAF; 
the main manifestation in both conditions is neurogenic orthostatic hypotension (NOH).(3) NOH 
is caused by impairment of autonomic reflexes that controls cardiovascular and neurohumoral 
adaptation to standing. Supine norepinephrine (NE) levels (normal in MSA and low in PAF) failed 
to increase upon standing. This leads to impaired sympathetic-mediated vasoconstriction that 
results in cerebral hypoperfusion(4) and symptoms such as lightheadedness, dizziness, syncope 
and falls(5) that contributes to morbidity, disability and death in this population.(6) 
I hypothesized that the pharmacological agent, atomoxetine, a norepinephrine transporter 
(NET) blocker that increases the availability of NE at the level of the synapse by blocking its 
reuptake,(7) could induce an increase in blood pressure and be a potential treatment for NOH in 
autonomic failure. In normal individuals, atomoxetine, which is approved for the treatment of 
attention deficit hyperactivity disorder, has minimal hemodynamic effects because of a balance 
between its central and peripheral actions on the autonomic nervous system.(8) In central 
autonomic pathways, the increased NE levels diminish sympathetic activity by stimulating α-2 
adrenergic receptors. In peripheral sympathetic fibers, the increased NE levels may stimulate 
sympathetic activity by acting on postganglionic α-1 adrenergic receptors.(9) Patients with 
autonomic failure have an imbalance between these central and peripheral autonomic pathways. 
In MSA, the peripheral sympathetic fibers are disconnected from its central input(10) unmasking 
any peripheral sympathetic-like effect and blood pressure response. 
In a proof-of-concept clinical trial,(11) I determined the effect of 18 mg of atomoxetine on 
seated and standing blood pressure in 21 autonomic failure patients (10 MSA and 11 PAF). These 
preliminary data showed that an acute dose of 18 mg of atomoxetine increased seated systolic 
blood pressure (SBP) by ~50 mm Hg compared with placebo in MSA. In MSA patients, 
atomoxetine increased plasma NE levels by 26% suggesting a mechanistic link between the 
neurohumoral response and its hemodynamic effect. No significant blood pressor responses were 
observed in PAF patients who had very low plasma NE.  
The sympathetic nervous system is maximally activated upon standing; plasma NE levels 
doubled on standing in normal subjects but failed to increase in autonomic failure patients. We 
hypothesized that atomoxetine by preventing the clearance of NE in the synapse would induce a 
greater blood pressure (BP) response upon standing compared with the direct α-1 adrenergic 
vasoconstrictor, midodrine. In a separate crossover study,(12) we compared the effect of a single 
dose of 18 mg of atomoxetine with midodrine (5,10 mg) and placebo on standing SBP and clinical 
symptoms in 69 patients with NOH and autonomic failure. Our results showed that atomoxetine 
and midodrine increased seated BP at the same magnitude. However, 18 mg of atomoxetine was 
more effective than midodrine in improving standing SBP (+7.5 mm Hg, figure 4C). Equally 
important, atomoxetine but not midodrine induced a significant reduction in clinical symptoms 
(lightheadedness and dizziness) compared with placebo, figure 5. Both studies strongly suggest 
that atomoxetine could be a potential treatment for NOH in autonomic failure, particularly in 


 
 
 
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patients with MSA.  Additional studies are needed to conclusively determine its potential 
therapeutic role for these patients. 
The response to an acute administration of a pressor agent, however, does not predict the 
long-term efficacy of the drug. We propose to test the hypothesis that prolonged (4-week) 
administration of the NET blocker, atomoxetine, improves clinical symptoms, activities of daily 
living, and increases standing blood pressure in patients with neurogenic OH. Repurposing 
atomoxetine for the treatment of NOH would be of a major advantage because this medication is 
commercially available, well-tolerated and previous pharmacoepidemiological studies(13,14) 
showed no increased risk of serious cardiovascular events among atomoxetine users. 
2.0 
Background 
Autonomic failure is a group of neurodegenerative diseases of unknown cause involving two 
main subtypes: 1) MSA in which autonomic impairment is combined with an extrapyramidal or 
cerebellar movement disorder or both, and 2) PAF in which autonomic impairment (that is, NOH 
and bladder and sexual dysfunction) occurs alone. Other types of autonomic failure include the 
autonomic impairment associated with Parkinson Disease (PD).(3) Table 1 demonstrates the 
clinical and pathophysiological differences between these forms of autonomic failure. The 
presence and nature of the autonomic and neurological abnormalities depend on the location of 
the pathological lesion known as α-synuclein deposits. In MSA, α-synuclein precipitates are found 
as glial cytoplasmic inclusions in basal ganglia or cerebellar structures.(1) These patients have 
impaired central autonomic modulation but intact postganglionic sympathetic fibers as evidenced 
by the near normal plasma NE levels and normal cardiac NE uptake.(15) In contrast, in PAF α-
synuclein deposits are located in neurons forming a characteristic pattern named Lewy bodies 
and are found in preganglionic and postganglionic sympathetic neurons as well as in autonomic 
ganglia.(2) Plasma NE levels are usually low in these patients.(16) The main clinical manifestation 
in MSA and PAF patients is NOH that results in cerebral hypoperfusion(4) and symptoms such 
as lightheadedness, dizziness, syncope and falls upon standing. In the early stages of the disease 
when NOH is the sole clinical presentation, MSA resembles PAF.(17) This period could last for 
years, measurement of plasma NE may help to identify patients with PAF, particularly when is 
very low (supine plasma NE<100 pg/ml), but this test has poor specificity and in the majority of 
cases it is inconclusive. A definitive diagnosis of PAF and MSA requires postmortem 
confirmation.(18) 
Prevalence of Autonomic Failure 
 Table 1. Clinical and pathophysiological characteristic in patients with MSA, PAF and Parkinson disease 
Findings 
MSA 
PAF 
Parkinson disease 
NOH 
+++ 
+++ 
+++ 
Movement disorder 
+++ 
- 
+++ 
Plasma norepinephrine 
Normal 
Low 
Low 
Cardiac noradrenergic uptake (MIBG or 
6-[18F]fluorodopa 
Normal 
Low 
Low 
Glial cytoplasmatic inclusions 
+++ 
- 
- 
Lewy bodies 
- 
++ 
++ 
MSA, multiple system atrophy; PAF pure autonomic failure. The presence of glial cytoplasmatic inclusions and Lewy bodies are 
detected during post-mortem examination. 


 
 
 
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 The precise prevalence of autonomic failure is unknown. Epidemiological studies are quite 
scarce and only available for MSA. In the Olmsted County, Minnesota, in the age group >50 years, 
the estimated annual incidence rate for MSA is 3 cases per 100,000 person-years.(19) 
Considering that the median survival is around eight years,(20) the estimated prevalence of this 
condition is 24 cases per 100,000 population. Similar prevalence has been reported in 
Europe.(21) Based on these data, it is predicted that approximately 21,000 individuals in the 
United States suffer from MSA (National prevalence was estimated using 2010 US census 
population estimates). The prevalence of PAF is thought to be lower than MSA, but there are no 
epidemiological data available to quantify the prevalence of this disease.  
Management of Neurogenic Orthostatic Hypotension in Autonomic Failure 
NOH is defined as a drop in SBP of at 
least 20 mm Hg or diastolic blood pressure 
(DBP) of at least 10 mm Hg within three 
minutes of standing or head-up tilt to at least 
60 degree angle.(22) These patients have 
also a poor compensatory increase in their 
heart rate because of impaired baroreflex 
function. The average fall in SBP upon 
standing was 70±30 mm Hg in 237 patients 
registered in the Vanderbilt Autonomic 
Dysfunction Center database. Figure 1 
shows continuous blood pressure and heart 
rate recordings in a typical patient with NOH 
caused by autonomic failure. In this 
particular case, the decrease in SBP was 
~53 mm Hg and the increase in hear rate 
(HR) was only 16 bpm during head up tilt 
(+70 degree tilt angle).  
The profound decrease in BP upon 
standing induced a decrease in cerebral 
blood 
flow 
that 
led 
to 
pre-syncopal 
symptoms such lightheadedness and dizziness.(4) These patients have higher risk for 
hospitalizations, falls and syncope.(23,24) A stepwise approach is recommended based on the 
severity of the symptoms.(6,25) The first step includes the use of non-pharmacological measures 
such as rapid water drinking, use of compression stockings or abdominal binders. Patients should 
avoid situations such as excessive heat exposure or prolonged standing and medications that 
can cause or exacerbate OH (e.g. tricyclic antidepressants, vasodilators). In the majority of 
patients, however, non-pharmacological measures are unable to control symptoms or reduce the 
frequency of syncope and falls. Therefore, the use of pharmacological agents such as short-acting 
pressor agents is often needed. (26) 
Since its approval by the FDA in 1996, the α1 adrenergic agonist, midodrine has been the 
current standard of care for the treatment of NOH OH. The efficacy of midodrine in improving 1-
minute standing SBP has been demonstrated in double-blind, placebo-controlled trials.(27,28) 
The use of midodrine, however, is limited in a fairly high number of patients by adverse effects 
such as pilomotor reactions (13%), pruritus of the scalp (10%), urinary retention (6%) and supine 
hypertension.(27,28) Furthermore, previous reports have described that midodrine may not work 
in a sub-group of patients with autonomic failure. In our single center’s experience, approximately 
36% of patients did not experience an increase in standing BP or improvement in OH-related 
Figure 1. Changes in heart rate (first channel) and 
continuous blood pressure (second channel) in a patient 
with NOH during 70 degree head up tilt.   


 
 
 
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symptoms, 60 minutes post-drug administration, despite receiving therapeutic doses of midodrine 
(5 or 10 mg).(12) This lack of response could be due to different degrees of sensitivity to vascular 
α-adrenoreceptors. 
In February 2014, the FDA approved droxidopa (L-dihydroxyphenylserine) a synthetic 
norepinephrine (NE) precursor for the treatment of NOH.(29) Droxidopa has a structure similar to 
NE but with a carboxyl group, it can be administered orally and is converted to NE through the 
enzyme dopadescarboxylase, which is found both centrally and in the periphery. The optimal 
dose varied between 300 and 1800 mg a day; patients require careful titration given different 
degrees of adrenergic denervation. This medication has been recently introduced in the market 
on September 2014; the long-term efficacy of this medication (beyond 2 weeks on therapy) for 
the treatment of symptomatic NOH is still under research. It is important to note that the two senior 
members of our group (Drs. Horacio Kaufmann and Italo Biaggioni (co-PI)) significantly 
contributed to the design, conduct, data interpretation and manuscript writing in the pivotal phase 
3 study that evaluated the effect of droxidopa on symptomatic NOH.(30) 
Significance 
NOH is a cardinal feature of generalized autonomic failure and commonly is the presenting 
sign in patients with autonomic failure. NOH is a debilitating condition that can substantially 
reduce the patient’s quality of life.(31) Patients commonly experience dizziness, syncope, or lose 
consciousness and fall, greatly increasing the risk of hip fracture and head trauma. These factors 
contribute to morbidity, disability, and death.(6,23) 
Treatment of autonomic failure is challenging, and therapeutic options are scarce. There are 
only 2 FDA-approved drugs for the treatment of this condition in the US: midodrine an alpha-1 
adrenergic agonist approved in 1996, and droxidopa a synthetic norepinephrine precursor 
approved in 2014. In 2010, the FDA proposed the withdrawal of midodrine from the market due 
to lack of evidence supporting its clinical benefit for the treatment of NOH.(32) This decision was 
revoked in 2012 pending the results of phase 4 clinical trials that address its clinical benefit.(33) 
It is still unknown, however, if this medication will remain in the market. Our single center’s 
experience indicates that this medication only works in a limited number of subjects. In our most 
recent study,(12) 36% of patients with NOH did not improve their standing blood pressure with 
midodrine. The use of midodrine is also limited by the development of side effects such as 
pilomotor reactions (13%), pruritus of the scalp (10%), urinary retention (6%), and supine 
hypertension (4%).(27,28) These factors contribute to the poor persistence on midodrine 
treatment; I reported that 43% of midodrine users do not refill their medication after the first month 
on therapy.(24) 
Droxidopa was introduced in the market on September 2014.(29) The beneficial effect of 
droxidopa past 2 weeks of treatment has not been determined. The long-term efficacy and safety 
of droxidopa is still under research. The use of this medication was associated with few cases of 
neuroleptic malignant syndrome in Japanese MSA patients because of its potential central 
pyrogenic effects.(34) Furthermore, droxidopa’s efficacy is decreased when used in combination 
with dopamine decarboxylase inhibitors such as carbidopa because of the decreased peripheral 
conversion of droxidopa to NE.(35) Carbidopa is commonly used in combination with levodopa 
(Sinemet) in MSA and Parkinson disease for the treatment of motor symptoms. Finally, the 
prohibited cost of this medication (~$5,072 for a 30-day supply) limits its availability for patients 
with limited resources. Hence, there is an urgent need to identify new pharmacotherapies for the 
treatment of NOH in autonomic failure.  
 
3.0 
Preliminary Data 


 
 
 
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04/22/2019 
 
A Proof-of-Concept Clinical Trial: Selective NET Blockade Increases Seated and Standing 
Blood Pressure in MSA  
The NET protein is responsible 
for ~90% reuptake of NE released in 
the synapse and is the primary 
mechanism 
by 
which 
the 
physiological effects of NE are 
terminated.(36) 
Atomoxetine, 
a 
selective NET blocker, increases NE 
concentrations 
by 
blocking 
its 
reuptake (figure 2, right panel).  In 
central autonomic pathways, the 
increased 
NE 
levels 
diminish 
sympathetic activity by stimulating α-
2 
adrenergic 
receptors 
(sympatholytic 
effect).(9) 
In 
peripheral sympathetic fibers, the 
increased NE levels may stimulate 
sympathetic activity by acting on postganglionic α-1 adrenergic receptors (sympathomimetic 
effect). The effect on BP depends on a tight balance between these central and peripheral effects. 
Healthy subjects do not have any significant changes in BP.(8)  
Our group hypothesized that 
treatment with a pediatric (18 mg) 
dose of atomoxetine should result 
in an increased BP in patients with 
autonomic 
failure, 
particularly 
MSA because of the balance 
between 
these 
central 
and 
peripheral autonomic pathways is 
lost.  
We recruited 21 patients with 
severe autonomic failure (10 with 
MSA and 11 with PAF) from 
referrals 
to 
the 
Autonomic 
Dysfunction Center at Vanderbilt 
University. All the studies were 
conducted in the morning, at least 
2.5 hours after breakfast to avoid 
any acute hemodynamic effects 
from eating, and in a postvoid 
state. On separate days, patients 
were given a pediatric dose of 
atomoxetine (18 mg) or placebo in 
a 
randomized, 
single-blind, 
crossover fashion. The study was 
conducted 
with 
the 
patients 
seated on a chair with their feet on 
Figure 3. Changes in seated systolic blood pressure (SBP) with 18 
mg of atomoxetine and placebo in patients with Multiple System 
Atrophy (MSA, A) and Pure Autonomic Failure (PAF, B). 
Figure 2.  Approximately 90% of NE released in the synapse is 
reuptake by the NET. This is the primary mechanism by which the 
biological effects of NE are terminated (left panel).  Atomoxetine is 
a selective NET blocker that increases NE concentrations in the 
synapse (right panel). 


 
 
 
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the floor. BP and HR were recorded every 5 minutes with an automated brachial 
sphygmomanometer. Data were digitally acquired into a custom-designed database. Baseline 
parameters were measured for 30 minutes, then we measured BP and HR upon standing. BP 
was measured for 60 minutes after drug administration, when peak plasma levels are achieved. 
We repeated BP and HR measurements upon standing at the end of this period, as described 
previously. 
Autonomic function tests performed at screening confirmed the diagnosis of autonomic failure; 
all subjects had severe sympathetic and parasympathetic involvement. As expected, patients with 
MSA had higher supine plasma NE and were younger as compared to patients with PAF (plasma 
NE 256104 vs. 7447 pg/ml; age 62±9 vs. 67±7 years old, P= 0.003, P= 0.06, (meanSD) 
respectively). There were no significant differences in body mass index, supine SBP, or 
orthostatic changes in SBP between groups. SBP significantly increased with atomoxetine 
compared with placebo in MSA (slope difference between the atomoxetine and placebo days 
0.92; 95% CI 0.73 to 1.11; P<0.001, figure 3A). In contrast, atomoxetine did not have a significant 
effect on SBP in PAF (slope difference between the atomoxetine and placebo days 0.16; 95% CI 
-0.02 to 0.34; P=0.08, figure 3B). In patients with MSA, atomoxetine increased seated SBP by 
54±26 mm Hg and standing SBP by 45±23 mm Hg at the end of the 60 minutes trial (compared 
to 2±13 mm Hg (seated) and 2±17 mm Hg (standing) with placebo, P=0.004 and P=0.016, 
respectively). The pressor effect of atomoxetine in MSA was in part explained by increased 
availability of NE. In these patients, plasma NE tended to increase with atomoxetine (from 
317±143 pg/mL at baseline to 430±83 pg/mL after atomoxetine, P=0.06).(11) Taken together, 
these findings offer a proof of principle to our hypothesis and additionally indicate that the use of 
atomoxetine is more effective in subjects with residual sympathetic function, measured by plasma 
NE levels, as was seen in MSA patients. 
Expertise in The Evaluation of OH-Related Symptoms and OH-Impact on Daily Activities 
 
Our group is experienced in the 
objective 
quantification 
of 
OH-
related symptoms. OH 
causes 
disabling symptoms that interfere 
with the ability to perform everyday 
physical 
activities. 
Classic 
symptoms 
of 
OH 
such 
as 
lightheadedness 
and 
dizziness 
occur when standing and disappear 
when lying down. Until recently, 
there was no widely accepted 
validated scale to assess the 
comprehensive symptom burden 
and severity of OH. Co-PI (Dr. 
Horacio Kaufmann) validated a 
novel clinical rating scale, the 
Orthostatic Hypotension Questionnaire (OHQ), table 2. The OHQ is composed of 10 individual 
items: 6 items measure specific symptoms (the Orthostatic Hypotension Symptom Assessment 
[OHSA]), and 4 items measure the impact of those symptoms on a patient’s daily activities (the 
Orthostatic Hypotension Daily Activity Scale [OHDAS]).(37) For the OHSA, patients are instructed 
to rate using a 0 to 10 point Likert scale (0 meaning “not experienced” and 10 meaning “worst 
possible”), how severe their symptoms for low BP pressure had been on average over the past 
week. For the OHDAS, patients are instructed to rate from 0 (no interference) to 10 (complete 
Table 2. Orthostatic Hypotension Questionnaire 


 
 
 
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interference) how the symptoms of NOH have interfered with daily life on average over the past 
week. The OHQ, composite score is calculated as the average, on a scale of 0 of 10, of the OHSA 
and the OHDAS composite scores.(37) Our group has experience using the OHQ, composite 
score during the conduct of the pivotal phase 3 study that led to the FDA approval of droxidopa 
for the treatment of NOH.(30)  
We propose to use the OHQ, composite score as the primary endpoint in our clinical trial. We 
will use OHSA, question 1 as a secondary endpoint because this question has been identified by 
the FDA’s Study Endpoints and Label Development (SEALD) core group as representing the 
cardinal symptoms of NOH and providing the best measurement of disease-defining symptoms. 
(29) 
Acute administration of atomoxetine increased standing systolic blood pressure to a 
greater extent than midodrine, the standard of care 
We previously reported that administration of 18 mg of atomoxetine increased BP in patients 
with MSA who are characterized by normal to high levels of plasma NE and residual sympathetic 
activity. In contrast, atomoxetine had no significant pressor effect in PAF patients who had very 
low levels of plasma NE. 
The 
sympathetic 
nervous 
system 
is 
maximally 
activated 
upon standing; plasma 
NE levels doubled on 
standing 
in 
normal 
subjects but failed to 
increase in autonomic 
failure 
patients. 
We 
hypothesized 
that 
atomoxetine 
by 
preventing the clearance 
of NE in the synapse 
would induce a greater 
BP 
response 
upon 
standing compared with 
the direct α-1 adrenergic 
vasoconstrictor, 
midodrine. Hence, we 
compared the effect of 
acute administration of 
18 mg of atomoxetine 
with midodrine (5 or 10 
mg) and placebo on 
standing SBP and OH-related symptoms as measured by OHSA composite score and question 
1 in autonomic failure patients with NOH.  
All studies were conducted in the morning, in a post-void state, at least 2.5 hours after 
breakfast to avoid the post-prandial hemodynamic effects. On separate days, patients were given 
atomoxetine (18 mg), midodrine (5 or 10 mg), or placebo in a randomized, single-blind, crossover 
fashion. Studies were conducted with the patients seated in a chair, with their feet on the floor. 
Figure 4. [A] atomoxetine and 
midodrine increased seated SBP 
(mean ±SEM) compared with 
placebo; [B] Post-drug seated SBP, 
recorded 60 min after administration 
of study drug; [C] Changes in 
standing SBP (standing SBP at 60 
min post-drug administration minus  


 
 
 
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We did not measure supine blood pressure during the study interventions because we followed 
standard of care (patients are instructed never to 
rest supine after receiving pressor agents). 
During baseline, we measured BP and HR 
every 5 minutes for 30 minutes. We also obtained 
orthostatic vital signs at 1, 3, 5 and 10 minutes or 
until tolerated. We asked the patients to rate their 
OH-related 
symptoms 
using 
the 
OHSA 
questionnaire.  We then administered the study 
drug, 
and 
hemodynamic 
parameters 
were 
assessed every 5 min for 60 min. We repeated the 
orthostatic vital signs assessment and symptom 
evaluation at the end of this period.  
 
We studied 69 patients with NOH (26 with PAF, 
21 with MSA, 12 with PD, and 10 with undetermined 
diagnosis). All patients had a profound decrease in 
SBP and DBP from the supine to the standing 
position (-63±29 and -29±16 mm Hg, respectively) without adequate increase in HR (+12±15 
bpm). NE levels were low in supine posture (126±89 pg/mL) and did not increase appropriately 
during standing posture (257±249 pg/mL). Both atomoxetine and midodrine increased seated 
SBP by ~ 20 mm Hg compared with placebo (figure 4A and 4B). However, atomoxetine was 
more effective in increasing standing SBP than midodrine (means difference = 7.5 mm Hg, 95% 
CI = 0.6 to 14.5, P=0.03), figure 4C. Furthermore, atomoxetine was the only drug effective in 
decreasing clinical symptoms as measured by OSHA (0.4 SQRT, 95% CI = -0.1 to -0.8, P = 0.02) 
and lightheadedness/dizziness, Q1 (0.6 SQRT points, 95% CI = -0.1 to 1.7, P = 0.03, figure 5), 
the study was published in Hypertension in 2014.(12) 
 
In the studies presented, we did not measure supine blood pressure during the study 
interventions because we followed standard of care (patients are instructed never to rest supine 
after receiving pressor agents). In the proposed study we will assess the effect of prolonged use 
of atomoxetine on supine blood pressure as a safety endpoint.  
      In summary, atomoxetine, a selective NET blocker, increases standing BP and improves 
OH-related symptoms to a greater extent than midodrine, the current standard of care. 
Atomoxetine could be a new therapeutic alternative for the treatment of NOH in patients with 
autonomic failure, particularly those with MSA. 
 
4.0 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
 
40 years old or older 
 
Neurogenic Orthostatic Hypotension (defined by a reduction of systolic blood pressure 
≥20 mmHg or a diastolic blood pressure ≥ 10 mmHg withing 3 minutes of standing or at 
least head-up tilt 60 degrees on a tilt table. 
Exclusion Criteria: 
 
Pregnancy or breastfeeding 
 
Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria, anaphylaxis) 
 
Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion), 
Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella 
(milnacipran) 
 
Previous history (within 14 days prior to enrollment) and current use of monoamine 
oxidase inhibitors 
Figure 5. Atomoxetine significantly decreased 
lightheadedness and dizziness (OSHA, 
question 1, Q1) compared with placebo. 
Midodrine did not improve symptoms.  


 
 
 
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04/22/2019 
 
Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine, 
fluoxetine, quinidine 
 
Pre-existing sustained severe hypertension (BP  140/90 mmhg in the sitting position at 
least two times 10 minutes apart) 
 
Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino 
transaminase [ALT] >2 x upper limit of normal range) 
 
Impaired renal function (serum creatinine equal or more than 1.6 mg/dl) 
 
Myocardial infarction within 6 months prior to enrollment 
 
Congestive heart failure (LV hypertrophy acceptable) 
 
History of serious neurologic disease such as cerebral hemorrhage, or stroke 
 
Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for 
follow-up visits, unlikelihood of completing the study, and mental conditions rendering 
the subject unable to understand the nature, scope, and possible consequences of the 
study 
 
Narrow-angle glaucoma 
 
5.0 
Enrollment/Randomization 
 
The proposed study consists of an open–label, dose-optimization phase followed by a 2x2, 
double-blind, placebo-controlled, crossover phase. We estimated that we need to enroll 77 
patients in the open–label, dose-optimization phase to have 40 responder patients randomized in 
the double-blind, placebo-controlled, 2X2 crossover phase (study procedures). We based our 
calculations on data collected during our previous study (preliminary data), the proportion of 
responders to atomoxetine was 64% (95% CI 52-76%) using the criteria proposed in the planned 
study.  Atomoxetine responders will be defined as those who: 1) had a decrease in self-rating 
scale of ≥1 point in the OHSA, question 1 and 2) had an increase in standing SBP equal or more 
than 10 mm Hg from baseline, 60 minutes post-drug administration. Our target population is 
autonomic failure patients with NOH.  
Patients with NOH and autonomic failure will be enrolled in two national referral centers that 
focus exclusively on disorders of the autonomic nervous system. The Vanderbilt Autonomic 
Dysfunction Center (PI: Dr. Cyndya Shibao) and the Dysautonomia Center at New York University 
(PI: Dr. Horacio Kaufmann).  
 
6.0 
Study Procedures 
Specific Aim: Hypothesis: Prolonged administration of the NET blocker, atomoxetine, 
improves OH-related symptoms and OH-impact on daily activities compared with placebo 
in patients with  autonomic failure and NOH. 
The proposed study consists of an open–label, dose-optimization phase followed by a 
randomized, double-blind, placebo-controlled, 2x2 crossover phase. The overall study design is 
presented in figure 6. The schedule of activities is presented in the Appendix.  
 
Screening (-10 day) 


 
 
 
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 After 
informed consent is obtained, each patient will undergo a complete medical history and physical 
examination, and routine safety laboratory analysis, including electrolytes and serum creatinine, 
complete blood count, complete metabolic panel, urinalysis, and EKG. Subjects will be withdrawn 
from other pressor medications for 5 half-lives prior to administration of study medications. All 
other medications, including fludrocortisone, will be held constant throughout the study.  
Evaluation of OH-related Symptoms and OH-impact on Daily Activities. We will use the 
OHQ composite score. Subjects will rate their presyncopal symptoms and daily activities, 7 days 
prior to enrollment.  
Orthostatic Standing Test. Study patients will be studied in the morning, under fasting 
condition after midnight, to avoid the confounding effect of post-prandial hypotension. We will 
obtain BP and HR measurements with automated sphygmomanometer twice while supine for 10 
min (with the torso and head elevated 30 degrees from horizontal) and after 1, 3, 5, and 10 min 
standing. The standing time will be measured with a chronometer. This initial measurement will 
allow us to determine if patients have NOH (inclusion criterion) and/or supine hypertension. 
Supine and standing plasma NE. We will collect supine and standing plasma samples to 
measure NE using high-performance liquid chromatography with electrochemical detection.(38) 
If the subject is unable to stand up, plasma NE will be collected after the subject sits up with his 
torso upright for at least 10 minutes. 
Autonomic Function Testing. All patients enrolled in this study will undergo autonomic 
function tests to determine the presence of autonomic failure. During these tests, we will monitor 
HR by EKG and BP continuously with tonometry or finger plethysmography and intermittently with 
an oscillometric device. These tests include sinus arrhythmia and valsalva maneuver. Deep 
breathing-vagally mediated sinus arrhythmia (SA) is assessed during controlled breathing 


 
 
 
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(pattern of 5 seconds inhalation and 5 seconds exhalation repeated over 90 seconds). Valsalva 
maneuver. The subject will exhale against a 40 mm Hg pressure. Changes in intrathoracic 
pressure produce autonomically modulated transient changes in HR and BP.  
Open-Label Dose-Optimization Phase (days -10 to -7) 
Procedures. We will test two doses of atomoxetine (10 and 18 mg) on separate days.  We 
will perform all the assessments in the morning, under fasting conditions, to avoid the confounding 
effect of post-prandial hypotension. We will obtain BP and HR measurements with automated 
sphygmomanometer twice while supine for 10 minutes (with the torso and head elevated 30 
degrees from horizontal) and after 1, 3, 5, and 10 minutes standing. We will ask the subject to 
rate his/her symptom using OHSA, question 1. We will administer atomoxetine (10 mg), and  60 
minutes after dose administration, we will repeat the BP and HR measurements, supine and 
standing, and symptom assessment using OHSA, question 1. If the subject does not meet the 
definition of atomoxetine responders using 10 mg of atomoxetine, then we will test 18 mg of 
atomoxetine using the procedures outlined above on a separate day.  
Atomoxetine responders will be defined as those who: 1) had a decrease in self-rating 
scale of ≥1 point in the OHSA, question 1; and 2) had an increase in standing SBP equal 
or more than 10 mm Hg from baseline, 60 minutes post-drug administration. 
Subjects will be excluded if they 1) reached the maximum permitted doses of 18 mg 
and have not responded to the medication as defined previously or 2) had sustained blood 
pressure >180 mm Hg systolic or >110 mm Hg diastolic while standing, sitting or supine 
two consecutive BP measures taken 15 minutes apart.  
Subjects will undergo a 7-day wash-out period after the completion of this phase.  
Randomized, placebo-controlled, crossover phase (days 0 to 64).   
A total of 40 subjects will participate in this study. We will recruit an equal number of male and 
female subjects. We will randomize the order of the medication assignment (atomoxetine or 
placebo) according to a computer-generated, randomization schedule. We will stratify the 
treatment assignment by clinical center and atomoxetine dose (10 or 18 mg twice a day). The 
investigational pharmacy will store, prepare, and label all the investigational agents, and maintain 
accurate drug storage and dispensing logs. At the time of randomization the research nurse will 
fax a copy of the consent form and a prescription containing the atomoxetine dose. The 
pharmacist will assign the subject a randomization number and provide the investigator with a 4-
week supply of the blinded study medication.  Upon completion of the 4-week treatment period 
(period 1), the investigator or research nurse will instruct the subject to discontinue the study 
medication for at least 1 week and a maximum time of 4 weeks (wash-out period). After this 
period, the subject will complete the second 4-week treatment period (period 2). During the 4-
week treatment periods (period 1 and period 2) we will closely monitor the subjects. We will 
perform telephone visits at 1, 3, 5, and 7 days during the first week on treatment followed by 
weekly telephone visits. We will work diligently with the patients and care givers to maintain them 
throughout each of the 4-week treatment periods. We will also measure the primary endpoint and 
secondary endpoints twice at 2-week (days 14 and 50) and 4-week (days 28 and 64) intervals for 
each period.  
 
Early crossover: 
The primary comparison will be between atomoxetine and placebo on the primary endpoint 
collected two and four weeks into the treatment period. We will allow patients to early cross over 
after 2 weeks of treatment for patients who cannot remain on study medication for 4 weeks.  


 
 
 
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Outpatient monitoring. A research nurse/fellow will communicate with the patient or spouse 
at days 1, 3, 5, and 7 during the first week on treatment and after that on a weekly basis while the 
patient is in period 1 and 2 of the randomized crossover phase. These phone calls will be 
performed to ensure that there are no clinical problems, to collect BP and HR information 
measured at home, to coordinate the recording of hemodynamic data (24-hr ambulatory BP 
monitoring), non-hemodynamic data (OHQ, fall calendar and the Columbia-Suicide Severity 
Rating Scale), and to ensure that the patient's safety is maintained.  
Hemodynamic evaluation 
BP assessment during study visits. These measurements will take place at days 0, 14, 28, 
36, 50, and 64 [before (pre-drug) and 60 minutes post-drug administration] during the randomized, 
placebo-controlled, crossover phase. We will perform all assessments in the morning, under 
fasting conditions, after midnight to avoid the confounding effect of post-prandial hypotension. We 
will obtain BP and HR measurements with automated sphygmomanometer twice while supine for 
10 minutes (with the torso and head elevated 30 degrees from horizontal) and after 1, 3, 5, and 
10 minutes standing.  
Ambulatory BP monitoring. We will perform a 24-hour ambulatory BP monitoring with a 
positional tracking device during the randomized crossover phase two weeks after the initiation 
of study drug (period 1: day 14; period 2: day 50). Study subjects will be instructed to remain 
seated for 4 hours after taking their morning dose of the study drug. The goal of this evaluation is 
to assess the magnitude of the pressor response beyond 1 hour after drug administration and 
after multiple dosing. If during the 4-hour monitoring period the patient’s seated BP is increased 
beyond our established safety threshold (180/110 mm Hg), they will be withdrawn from the study 
with their primary endpoint taken at the exit visit. 
Non-Hemodynamic Evaluation 
Assessment of OH-related symptoms and OH-impact on daily activities. We will perform 
the OHQ composite score at 0, 14, 28, 36, 50, and 64 days (primary endpoint, figure 6).  
Tracking of falls: We will use the calendar method of falls reporting which is considered the 
gold standard.(39) A fall will be defined as any event in which any part of the body above the 
ankle hits the floor, the ground, or a lower surface, including falls that occur on stairs. Patients will 
be trained at the baseline visit to record their experiences on the calendar each day, either placing 
an "N" in the box for the appropriate day if no fall has occurred that day or placing an "F" in the 
box if a fall has occurred that day. We will monitor the occurrence of falls at 0, 14, 28, 36, 50, and 
64 days. 
Standardization of care. Subjects will be provided written instructions on how to prevent 
supine hypertension, these include not resting supine in a horizontal position after taking the 
medication. Alternatively they can rest with the head of the bed elevated. Safety: Administration 
of concurrent monoamine oxidase inhibitors could result in a severe increase in BP. Therefore 
participants in this study will be provided a medical safety bracelet indicating that the subjects is 
participating in a clinical trial that involves the use of a norepinephrine transporter inhibitor 
(atomoxetine). Subject will wear this bracelet for the duration of the randomized crossover phase.  
Evaluation of side effects: The study nurse will contact the patient at days 1, 3, 5, and 7 
during the first week on treatment and after that on a weekly basis while the patient is in periods 
1 and 2 of the randomized, placebo-controlled, crossover phase. The study nurse will inquire 


 
 
 
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about side effects during the study periods. We will use structured case report forms to assess 
compliance, concurrent medications, medical conditions, and adverse events.(40) Structured 
checklists are more effective in detecting adverse medication events than open-ended questions. 
All side effects will be reported and analyzed according to FDA guidelines.(41) 
 
Endpoints  
Efficacy measure: The primary endpoint will be the change from baseline of the OHQ, 
composite score. The OHQ will be administered during screening, before each treatment period, 
2 weeks into the treatment period, and at the end of each of the 4-week treatment period (days 
0, 14, 28, 36, 50, and 64, figure 6). Secondary endpoints include the improvement in the Likert 
scale for “dizziness, lightheadedness, feeling faint, or feeling like you might black out” (OHSA, 
question 1), the increase in standing SBP, 60 minutes post-drug administration compared to 
baseline, frequency of falls, plasma NE. 
Safety will be assessed by adverse events. 
Study-related visits or telephone communications will be scheduled within +/-3 
calendar days of the schedule. 
 
7.0 
Statistical Considerations 
Sample size justification: The primary endpoint is the change from baseline of the OHQ, 
composite score. In a study (30) co-authored by Dr. Horacio Kaufmann one of the study’s PIs, 
droxidopa group had a mean (SD) change of -1.83 (2.07) units in OHQ composite score, versus 
-0.93 (1.69) in the placebo group. Assuming a similar effect will be achieved by atomoxetine, a 
sample size of 35 will give us 86% power to detect a difference in means of -0.9 (-1.83 versus -
0.93), assuming a standard deviation of 1.7 for the within-subject differences using a paired t-test 
at 0.05 type I error rate. Assuming an about 10% drop-out rate, we plan to enroll 40 subjects.  For 
our secondary endpoint, the increase in standing SBP, 60 minutes post-drug administration, our 
study sample size has >90% power to detect a difference of 45±23 mm Hg (preliminary data)(11) 
between placebo and atomoxetine. 
 
Data analysis plan 
 
For both primary and secondary endpoints, standard graphing and screening techniques will 
be used to detect outliers and to ensure data accuracy. Summary statistics for both numerical 
and categorical variables will be reported by study sequences to describe the study sample. 
Comparability among randomization sequences will be assessed. 
The primary comparison will be between atomoxetine and placebo on the primary endpoint 
collected two and four weeks into the treatment period. It is important to note, however, that we 
may not be able to keep patients from crossing over to active treatment for those on placebo for 
the entire 4 weeks. Such crossover may bias the atomoxetine versus placebo comparison at week 
4. However, from our past experience we are confident that we can keep patients on placebo for 
at least 2 weeks and will work quite diligently with the patients to keep them for 4 weeks. Thus, 
week 2 analysis will be primary. To avoid potential bias introduced by potential unblinding by such 
crossover, the primary endpoint OHQ will be collected by the study personnel who are blinded 
from such crossover information. The intention-to-treat analysis will be the primary analyses, and 
the per-protocol analysis will be secondary. Before data unblinding, the PI (Dr. Cyndya Shibao) 
and the study statistician and co-PI (Dr. Chang Yu) will review all protocol deviations and 
determine a list of protocol violators to be removed for the per-protocol analysis. 


 
 
 
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We will use a 2x2 crossover design. Although we have designed the study to avoid carry-over 
effect by having a one-week washout period, we will test for potential carry-over effect using the 
T-test approach described in Section 2.3 (page 21) of Jones and Kenwood (2003).(42) If there is 
evidence for a carry over effect, the traditional safe approach is to use data collected before the 
crossover to estimate the treatment effects. This would result in a loss of power; however it would 
ensure valid estimates. While we will use this approach in our analyses, we also planned to 
measure the primary endpoint right before study subjects take study medication (atomoxetine or 
placebo) at day 0 and at day 35 for the two treatment periods, respectively. These baseline 
measurements will allow us to estimate any residual carry over effect. This estimate will enable 
us to assess the atomoxetine versus placebo difference using data collected in both crossover 
periods in the presence of residual carry over effect.  
 
The primary efficacy analysis will be unadjusted. We will calculate within-subject mean 
differences and 95% confidence intervals for the atomoxetine versus placebo comparison and 
test for treatment effect using paired t-test or Wilcoxon signed rank sum test depending on 
whether the data are normally distributed. 
 
Additional adjusted analyses will be conducted using mixed effects models with a random 
subject effect and with treatment (atomoxetine versus placebo) as the fixed effect. We will include 
age and gender as covariates in the model.  The secondary endpoints will be analyzed similarly 
as for the primary endpoint. 
 
Due to the pharmacy error, at the end of the study, we will have lower dose (10mg) A and the 
higher dose (18mg) A (the doses with error used on patients until May 2018) and lower dose 
(10mg) B and the higher dose (18mg) B (the doses correctly compounded) versus placebo on 
each crossover. Our original plan is to pool the lower dose (10mg) B and the higher dose (18mg) 
B together for the paired treatment versus placebo comparison. Now we still plan on pooling all 
four doses together for the comparison. However, we will assess if there is any difference on 
safety and efficacy between A and B for the two doses separately. Based on the mechanism of 
action, we do not expect a difference between A and B for either dose. If we observe a difference, 
including lower dose (10mg) A or higher dose (18mg) A in the treatment versus placebo 
comparison will either enhance or attenuate the treatment versus placebo difference. We will 
report their impact accordingly in our findings. 
 
Safety endpoints such as adverse events will be reported and analyzed according to FDA 
guidelines.(41) 
 
We do not plan to conduct an interim analysis. We will have a Data and Safety Monitoring 
Board (DSMB) to independently monitor the conduct of the trial. 
 
8.0 
Risks 
 
1. Supine hypertension: Around 50% of patients with autonomic failure develop supine 
hypertension.(43) Atomoxetine may induce or exacerbate supine hypertension particularly 
in patients with MSA. We designed our protocol to minimize this risk. First, we will only 
recruit patients who have seated BP less than 140/80 mm Hg. Second, we will use the 
minimal effective atomoxetine dose either 10 or 18 mg (pediatric dose). Third, we will 
exclude patients whose BP has increased above 180/110 mm Hg, 60 minutes after drug 
administration (safety threshold). Fourth, we will provide the patients with written 
instructions on how to prevent supine hypertension. These include not to rest supine on a 


 
 
 
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horizontal position after taking their medication. We will ask the patient to check their blood 
pressure at home with a calibrated automatic BP monitor. We will instruct subjects to rest 
with the head of the bed elevated at least 30 degrees, and we will monitor their BP at 
home on two occasions with a ambulatory BP monitor with a tracking position device.  
 
2. NET blockade such as atomoxetine can cause severe hypertension when taken together 
with monoamine oxidase inhibitors. For this reason, subjects will be asked to wear a 
medical alert bracelet stating that they should not be given a monoamine oxidase inhibitor 
without first contacting the PI. Common (>10%) side effects associated with atomoxetine 
are headaches (2% to 19%), insomnia (2% to 15%), somnolence (4% to 11%), xerostomia 
(21%), nausea (7% to 21%), abdominal pain (7% to 18%), appetite decrease (11% to 
16%), and vomiting (3% to 11%). Research subjects will be informed of all the potential 
side effects associated with the drug. During the randomized crossover phase, a research 
nurse will contact the patient on a weekly basis to collect information about potential 
adverse events. All potential adverse events will be ranked according to severity and will 
be reported according to the data and safety-monitoring plan described below. 
 
3. Atomoxetine has been associated with suicidal ideation in children. The frequency of 
suicidal ideation is 0.37% (5/1,357) based on a recent meta-analysis. We have 
implemented a monitoring plan for prospectively assessing suicidal ideation and behavior 
The overall purpose of this plan is to ensure that any patient enrolled in the randomized 
crossover treatment phase who experiences suicidal ideation and behavior is properly 
recognized and adequately treated. For this purpose, we will use the C-SSRS survey for 
prospectively assessing suicidal ideation and behavior during at baseline (prior to 
randomization) and at the end of period 1 (day 28) and period 2 (day 64).  
 
9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
Any protocols will be reviewed and approved by the Vanderbilt Institutional Review Board (IRB) 
before any subject is enrolled. The PI will be responsible for ensuring both data integrity and for 
ensuring that study participants are safely cared for and that all AEs are noted, followed, and 
reported to the IRB, the DSMB, and the FDA. We will use the Guidance for Industry and 
Investigators for safety reported requirements for INDs and BA/BE studies published in the FDA 
website:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf  
 
Definitions: 
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug 
in humans, whether or not consider drug related. 
Suspected AE means any AE for which there is reasonable possibility that the drug caused the 
AE; “reasonable possibility” means there is evidence to suggest a causal relationship between 
the drug and the AE. An AE will be considered unexpected if it is not listed in the investigator 
brochure. 
Serious AE means any AE that: a) results in death, b) is life-threatening, c) requires inpatient 
hospitalization or prolongation of existing hospitalization, d) results in persistent or significant 
disability or incapacity, e) is a congenital anomaly or birth defect.  
 


 
 
 
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Serious adverse events will be reported to the Chairman of the Data and Safety Monitoring 
Board (DSMB), the IRB, and the FDA no later than 7 calendar days after the PI’s initial 
receipt of the information. 
 
Suspected AE interpretable as single case  (uncommon and strongly associated with drug 
exposure) will be reported to the FDA within 15 days from initial receipt. 
Non-serious, unexpected adverse events will be reported to the IRB at the time of the 
annual continuing review.  
 
Data and Safety Monitoring Board: The DSMB will provide objective review of treatment 
results as they relate to human safety and data quality. The committee will be comprised of   
Cheryl Laffer, M.D., Professor of Medicine, Division of Clinical Pharmacology; William DuPont, 
Ph.D., Professor of Biostatistics; Charles M. Stein, M.D., Professor of Clinical Pharmacology; and 
Ronald L. Cowan, M.D., Professor of Psychiatry. The DSMB will meet at least 3 times, once to 
review and ratify its charter and every 12 months to receive reports of the progress of the study. 
These reports will provide information regarding recruiting, safety reporting, data quality, and 
efficacy. The committee will assess safety data including development of hypertension, common 
adverse events, hospitalizations and other serious adverse events. The randomization will be 
blinded and presented on a coded basis (i.e. treatment periods, I and II) unless the Committee 
votes to receive unblinded data. The Committee will have the authority to modify the protocol or 
to terminate the study if it deems such actions to be warranted. The DSMB will provide summary 
reports to the IRB, the FDA and the investigators. The DSMB will review all serious adverse 
events. Committee members will be provided with all clinical data regarding the clinical 
occurrence. During regularly scheduled meetings, the DSMB will also be provided with a list of 
non-serious adverse events. The DSMB may choose to become unblinded; however, it is 
expected that such unblinding would not occur without reasonable concern related to either 
patient safety or data validity. 
 
All studies will be registered in ClinicalTrials.gov prior to enrolling subjects.  
 
Study Withdrawal/Discontinuation 
Criteria for study withdrawal/discontinuation 
 
 
Drug-related toxicity 
 
Requirement for prohibited concomitant medications (see exclusion criteria) 
 
Pregnancy 
 
Request by subject to terminate treatment 
 
Clinical reasons believed life threatening by the physician, even if not addressed on 
the potential risk section 
 
Blood pressure more than 180/110 in any position (standing, seated, or lying down) 
on two consecutive readings within 15 minutes 
 
10.0 
Privacy/Confidentiality Issues 
 
All data will be collected specifically for the proposed research project. A unique identification 
case number will be used to protect the confidentiality of the study participants. Only case 
numbers will be included in spreadsheets used for the statistical analysis. PHI and access to the 
key for the ID numbers will only be viewable by members of the research team. Member of the 
research team will have access to the patient's medical record during the screening visit and 


 
 
 
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throughout the study until the patient completes her participation in the study or meets any of 
the criteria for study withdrawal/discontinuation. 
 
11.0 
Follow-up and Record Retention 
 
Research records will be maintained for at least three (3) years from the date the research is 
closed with the Vanderbilt University IRB. All research records will be accessible for inspection 
and copying by authorized representatives of the IRB, federal regulatory agency 
representatives, and the department or agency supporting the research. 
 
All Health Insurance Portability and Accountability Act (HIPAA)-related documentation will be 
maintained for at least six (6) years from the date of the last use or disclosure of the Protected 
Health Information (PHI). 
 
12.0 
Data Coordinating Center 
Given the study will recruit patients from two sites, Vanderbilt University Medical Center (VUMC) 
and New York University Medical Center (NYUMC), that effectively turns the study into a 
multicenter clinical trial. We plan to establish a Data-Coordinating Center (DCC) within this two-
center RCT.  
 
The DCC under Dr Yu’s leadership proposes to serve the study by: 
[a] Providing Biostatistical Expertise. The DCC will input on all biostatistical aspects of the 
clinical trial, including optimizing study design for increased accuracy and precision, assessing 
at the beginning and re-evaluating statistical power should the DSMB make such request, 
conducting the statistical analyses, serving as the central repository for data generated from the 
two clinical centers (VUMC and NYUMC), collaborating on presentations/publications, and 
preparing reports for the DSMB. 
 
[b] Along with the trial coordinator, implementing and managing a REDCap database for the two 
study sites. The DCC will establish and manage a secure and confidential computerized system 
utilizing the REDCap to collect and manage study data. The REDCap is described in the 
resources section. It is a state-of-art system developed by a consortium of Clinical and 
Translational Science Research (CTSR) awardees led by Vanderbilt University. 
 
[c] Coordinating and standardizing trial conduct among the two sites. The DCC will collaborate 
with PIs on protocol development and implementation, preparing the standard operating 
procedure, conducting training sessions on standard data collection and data entry, quality 
assurance, and generating reports for the DSMB and the funding agency. 
 
Dr. Yu will assume the overall leadership for the DCC and will be directly involved with all 
biostatistical aspects for the program, except for unblinding the treatment should the DSMB 
request such. The staff statistician (TBN) will carry out much of the day-to-day operations and 
she/he may be unblinded. Should unblinding happen, the staff statistician will no longer be 
involved with any decision making for the trial to ensure the integrity of the study.  Since we can 
leverage our past experience on the REDCap database described in [b] above, the DCC will 
primarily focuses on the biostaitstical aspects of the study.  
 
 


 
 
 
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Appendix: 
Schedule of Study Activities 
 
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