Clinical trial NCT03808740
Conditions: Orthostatic Intolerance
Sponsor: Vanderbilt University Medical Center
Start date: 2018-07-01; Completion date: 2021-05-31
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
More than 78 million adults in the U.S. are obese. Bariatric surgery is the only modality that results in sustained weight loss along with reversal of diabetes mellitus, and a decrease in cardiovascular events. Obesity is associated with increased sympathetic nervous system (SNS) activity that contributes to blood pressure regulation; sympathetic vasoconstrictor activity is maximally activated upon standing and is fundamental for the maintenance of orthostatic tolerance. After bariatric surgery, there is a significant and sustained reduction in SNS activity at three and six months after the procedure, which is related to weight loss. Recently, multiple retrospective studies have reported an orthostatic intolerance (OI) syndrome after bariatric surgery characterized by chronic pre-syncopal symptoms, syncope and orthostatic hypotension. In the Vanderbilt University Medical Center bariatric surgical center, 741 post-bariatric surgery patients reported OI symptoms, 98 (13.2%) of these patients, progressed to chronic OI and in17 cases, the OI was so disabling that patients initiated treatment with pressor agents. More than 50% of OI cases in the cohort developed the condition during a weight-stable period. Hence, investigators propose the novel hypothesis that after bariatric surgery, the persistent reduction in SNS activity contributes to impaired orthostatic tolerance, which is independent of weight loss.

Detailed description:
Considering that SNS vasoconstrictor activity depends on synaptic norepinephrine concentrations, investigators propose a proof-of-concept study to test the hypothesis that the norepinephrine transporter (NET) inhibitor, atomoxetine, which increases synaptic norepinephrine concentrations, will improve post-bariatric OI. Understanding the changes in SNS activity and its contribution to orthostatic tolerance after bariatric surgery is of utmost importance to unravel the mechanisms of a novel and unrecognized syndrome, post-bariatric OI. In 2014, nearly 200,000 individuals in the US underwent bariatric surgery, and the number of bariatric surgery procedures is expected to increase by 22% each year. It is projected, therefore, an increase in the incidence of post-bariatric OI.

Participants with Roux-en-Y gastric bypass (RYGB) and Vertical sleeve gastrectomy (VSG) will be studied.

OI is a chronic and disabling condition; treatment is challenging because current therapies have debatable efficacy.

The proposed application will not only provide central knowledge on the pathophysiology of this new syndrome but also will fill an unmet therapeutic need by repurposing NET inhibitors for the treatment of OI.

Arms: arm 1: Participants with standard of care RYGB will receive atomoxetine, 0.5 mg/kg/day for 3 days arm 2: Participants with standard of care VSG will receive atomoxetine 0.5 mg/kg/day for 3 days arm 3: Participants with standard of care RYGB will receive placebo 0.5 mg/kg/day for 3 days arm 4: Participants with standard of care VSG will receive placebo 0.5 mg/kg/day for 3 days
Interventions: intervention 1: Atomoxetine intervention 2: Placebo
Intervention descriptions: intervention 1: atomoxetine 0.5 mg/kg/day. intervention 2: sugar pill

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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Orthostatic Intolerance After Bariatric Surgery 
 
 
Principal Investigator: Cyndya A. Shibao, MD 
Division of Clinical Pharmacology/ 
Department of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
Co-investigator: Naji N Abumrad, Sawyers Professor of Surgery, Department of Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Risks of Investigational Agents/Devices (side effects) 
7.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others 
8.0 
Study Withdrawal/Discontinuation 
9.0 
Statistical Considerations 
10.0 
Privacy/Confidentiality Issues 
11.0 
Follow-up and Record Retention 
References 


 
 
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1.0 
Background 
More than 78 million adults or ≈36% of U.S. adults are obese with medical costs estimated to be $210 
billion annually. Bariatric surgery is the only modality that results in sustained weight loss along with 
reversal of type 2 diabetes mellitus (T2DM), improvements in cholesterol biosynthesis, lipoprotein 
metabolism, and decreased cardiovascular events.1 In 2014, nearly 200,000 individuals in the US 
underwent bariatric surgery and each year the number increases by 22%.  
We2 and others, 3, 4 showed that obesity results in an increased sympathetic (SNS) activity decreased 
parasympathetic (PNS) activity and altered baroreflex sensitivity. Previous studies showed that bariatric 
surgery significantly reduces sympathetic activity. Vertical sleeve gastrectomy (VSG) decreases SNS as 
measured by direct sympathetic nerve recording at 6 and 12 months post-surgery.5 Roux-en-Y gastric 
bypass (RYGB), the most common bariatric procedure, also reduces SNS at 3 and 6 months post-
surgery.6 The mechanism underlying these sympatholytic actions are not completely understood but were 
found to be associated with a decrease in visceral fat7 and leptin levels.5 Regardless of the mechanism(s) 
involved, the reduction in SNS activity induces a decline in blood pressure in post-bariatric surgery 
patients8, which can have in some cases deleterious effects.  Importantly, a previous study showed mild 
orthostatic hypotension in otherwise asymptomatic post-bariatric subjects.9 
Recent retrospective studies and case series reported an orthostatic intolerance (OI) syndrome 
characterized by symptoms of cerebral hypo perfusion upon standing associated with pre-syncope and 
recurrent syncope.10-14 Our recent preliminary data support these findings; in our center, we performed 
4,906 bariatric procedures (78.4% RYGB and 19.7% VSG) in the past 20 years. Patient’s follow up after 
surgery is reduced to ≈15% at 5 years. Despite this attrition, 741 post-bariatric surgery patients, reported 
symptoms of OI. Chart review showed that 98 (13.2%) of these patients, progressed to chronic OI 
unexplained by anti-hypertensive use, vitamin deficiency or fluid loss. In 17 cases, the OI is so disabling 
that patients had to be treated with pressor agents such as midodrine and fludrocortisone. 
Normally, after assuming the upright position gravitational forces shift about 700 ml of blood volume 
to the lower part of the body, particularly the splanchnic circulation;15 to compensate for the decrease in 
venous return,  the SNS is maximally activated to induce vasoconstriction. We, therefore, hypothesize 
that the decrease in SNS activity in post-bariatric subjects results in insufficient vasoconstriction 
upon standing, causing patients to have OI.   
 
2.0 
Specific Aims 
Specific Aim 1:  To test the hypothesis that bariatric surgery (RYGB and VSG) impairs 
sympathetic vasoconstrictor activity and lead to the development of orthostatic intolerance 
independent of weight changes. 
Specific Aim 2: To test the hypothesis that potentiating sympathetic vasoconstrictor activity will 
reverse the impaired orthostatic tolerance post-bariatric surgery.  
 
3.0 
Inclusion/Exclusion Criteria 
We will recruit obese patients that will undergo bariatric surgery and medical weight loss from the 
Vanderbilt Center for Weight Loss (VWL). We will study three groups before and after 10% weight loss 
(15 RYGB, 15 VSG, and 15 medical weight loss). 
 
  
 


 
 
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Inclusion criteria 
• 
Obese subjects that will undergo bariatric surgery or medical weight loss. 
• 
Age 18-65 years 
• 
BMI >35 kg/m2 
• 
Weight < 400 lbs 
 
Exclusion criteria:  
Subjects presenting with any of the following will not be included in the study: 
• 
Diabetes type 1 
• 
Use of an alpha blockers, clonidine, beta-blockers.  
• 
Pregnancy or breast-feeding. Women of childbearing potential will be required to have undergone 
tubal ligation or to be using an oral contraceptive or barrier methods of birth control.  
• 
The use of any strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine, tipranavir). 
• 
Use of selective NET inhibitors. 
• 
Use of monoamine oxidase inhibitors. 
• 
Cardiovascular disease such as myocardial infarction within six months prior to the study, 
presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular 
hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree 
heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy  
• 
History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic 
attack  
• 
Hematocrit < 34%  
• 
Any underlying or acute disease requiring regular medication which could possibly pose a threat 
to the subject or make implementation of the protocol or interpretation of the study results 
difficult  
• 
Mental conditions rendering a subject unable to understand the nature, scope and possible 
consequences of the study  
• 
Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up 
visits, unlikelihood of completing the study, and investigator discretion  
 
4.0 
Enrollment/Randomization 
Recruitment and informed consent:  
We will recruit obese patients that will undergo bariatric surgery and medical weight loss from the 
Vanderbilt Center for Weight Loss (VWL). The VWL clinic is the largest bariatric surgery facility in 
Tennessee and annually performs ≈500 bariatric surgeries. We may also recruit persons willing to 
participate in the Jenny Craig weightloss program for 6 weeks. We will use research match and subject 
locator as well as an online pre-screening survey. We will use printed consent and e-consent to consent 
the subjects, for the two, parallel-arm, placebo-controlled portion of the study. We will randomize 1:1 to 
either placebo vs. the NE-transporter inhibitor, atomoxetine, at doses of 0.5 mg/kg/day. 
 
5.0 
Study Procedures 
   Pre-screening survey: Potential participants may choose to complete a pre-screening survey that will 
better evaluate their eligibility. Subjects may complete the survey on their own or while in clinic. 
    
Screening evaluation: Patient will be consented by phone. We will review the pre-surgical evaluation to 
assess for inclusion/exclusion criteria and we will invite to complete additional visits in the center for 
surgical weight loss or the autonomic cardiovascular suite.   


 
 
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Visit 1: Baseline (pre-surgery, RYGB/VSG) or pre-hypocaloric diet (medical weight loss). 
Visit 2: After 10% weight loss. The time is variable (RYGB/VSG= 10-12 days; medical weight loss 
group= ~30-40 days). 
Visit 3 (only for RYGB and VSG groups): 3-months after the bariatric procedure. 
Visit 4 (only for RYGB and VSG groups): After 3-days on stable doses of Strattera (atomoxetine) vs. 
matching placebo. For the two, parallel-arm, placebo-controlled portion of the study. We will randomize 
1:1 to either placebo vs. the NE-transporter inhibitor, Strattera (atomoxetine), at doses of 0.5 mg/kg/day. 
Visits 1-4 specific procedures:  
In supine position, we will measure: 1) plasma volume assessment; 2) continuous beat-to-beat blood 
pressure, and heart rate monitoring; 3) muscle sympathetic nerve activity (MSNA) with 
microneurography (at the physician’s descretion), 4) blood volume assessment; and 5) supine plasma 
catecholamines and metabolites.2, 16 We will assess orthostatic tolerance using tilt table testing.17, 18 We 
will perform a 60o head-up tilt (HUT) for 30 min until pre-syncope (defined as systolic BP (SBP, mm Hg) 
<80 or SBP>90 and pre-syncopal symptoms (nausea, lightheadedness, dizziness).19 We will repeat plasma 
catecholamines at the end of the 30 min HUT and hemodynamic measurements throughout the HUT. The 
supine and 60o HUT plasma catecholamines will provide information on orthostatic-induced sympathetic 
neuro-hormonal activation. We will use the ratio dihydoxyphenylglycol (DHPG) to NE as the biomarker 
for NET inhibition as we previously reported.20 We will repeat the serum pregnancy test (if applicable). 
We will wait 24 hours to perform visits 1-4 if  the patient has received IV fluids for clinical care. 
Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 30o 
HUT until pre-syncope 
Justification for Strattera dose and frequency. We selected a weight-adjusted dose (0.5 mg/kg/day or 
equivalent to 40 mg/day) because body weight has a significant impact on Strattera pharmacokinetics.21 
The weight-adjusted dose will provide comparable exposure between patients of different body sizes, 
which is of particular importance in the obese post-bariatric population. The T½ of atomoxetine is 5.6 
hours,21 hence we will study subjects after 3-day treatment to achieve stable concentrations. Specific 
procedures for visit 4 will be performed two hour after intake of blinded study medication. Atomoxetine 
reaches maximum plasma concentration within two hours after administration. 
The PI (Dr. Cyndya Shibao) holds an IND (117394) for the use of Strattera (atomoxetine) for indication 
other than attention deficit hyperactivity disorder.    
 
6.0 
Risks 
 
Blood Draws: Subjects may experience discomfort, bruising, and/or bleeding, or infection at the needle 
insertion site after a blood draw.  Rarely, some people faint. Frequent blood sampling may cause anemia. 
We will exclude subjects with hematocrit <34% 
 
12-hour fast: Participants may experience hunger during a 12-hr fast, however this is a standard 
requirement by clinicians for accurate blood testing. 
 
Study medication: NET blockade such as Strattera 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 Strattera are headaches (2% to 19%), insomnia (2% to 


 
 
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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. All potential adverse events will be ranked according to 
severity and will be reported according to the data and safety-monitoring plan described below. 
 
Strattera 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. Because subjects will only receive acute doses of 
Strattera, the risk of suicidal ideation is minimal. 
 
Intravenous Cather Insertion:  
Inserting a plastic catheter into the vein may cause a brief amount of pain and possibly a small bruise at 
the site, but will allow us to draw blood without repeated sticks throughout the study. It is also possible to 
develop an infection at the location of the catheter. It is uncomfortable to have the intravenous catheter in 
place for any length of time because it causes discomfort when the patient moves their arm. 
 
Tilt table testing:  
The potential risks associated with this procedure are: 1)  subjects may experience low back pain after 
lying down on the tilt table test; 2) there is a risk of syncope and/or low blood pressure. These events, 
however are expected considering that the procedure intend to cause evaluate orthostatic intolerance. We 
have specific rules for when to stop the procedure and move subjects to recumbent position (pre-syncope 
defined as SBP<80 mmHg or SBP>90 mmHg and pre-syncopal symptoms (nausea, lightheadedness, 
dizziness). 
 
Muscle Sympathetic Nerve Activity: 
The potential risk associated with this procedure are: 1) numbness sensation and/or pain in the area of 
nerve stimulation and/or needle insertion; 2) discomfort when the patient moves his/her leg; 2) potential 
risk of infection in the site of needle insertion. We will minimize these potential risks by applying sterile 
technique for needle insertion. Dr. Shibao has significant experience in the use of this technique and will 
choose which subjects will have the procedure.  
 
Blood volume assessment: 
As part of this research study, participants will receive a small amount of radioactive substance called 
Iodine-131.  Iodinated I-131 albumin (Volumex®), injected intravenously for determination of total 
plasma volume, is a radiopharmaceutical and, as such, requires that care be taken to ensure minimum 
radiation exposure consistent with proper patient management.  Each 1 ml dose of Volumex® contains 25 
microcuries in a pre-filled injection kit.  This radioactive substance will expose participants to a small 
amount of radiation (x-rays).  The radiation dose that they will receive from each procedure is about the 
same amount that they would receive over a period of four months from natural background radiation. 
Natural background radiation comes from naturally occurring radioactive material that is present in 
everyone’s body, from outer space (cosmic radiation), and from naturally occurring radioactive material 
in soil, rocks, and building materials.  This procedure will be performed a maximum of two times at an 
interval of at least several weeks.  I-131 tagged human albumin is a human blood product.  This product 
has been screened and heat-treated for at least 10 hours at 60C.  Experts demonstrated that this treatment 
kills the encapsulated viruses (like HIV and Hepatitis C). Recent studies have shown that the risk of 
getting a disease from human blood products such as this is extremely small.  However, some individuals 
may not want to receive human blood products for religious or other ethical concerns.   
 
Breach of Confidentiality: 
In the event of a security breach, confidential information may be stolen. We have strong security 
procedures in place to minimize the possibility of a breach.  Although we cannot provide a 100% 


 
 
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guarantee that the participant’s data will be safe, our procedures minimize the chance that a breach would 
take place. 
 
There is no benefit of the proposed research to the subjects per se.  
 
7.0 
Reporting of Adverse Events (AEs) or Unanticipated Problems involving Risk to 
Participants or Others 
 
All protocols will be reviewed and approved by the Vanderbilt Institutional Review Board (IRB) before 
enrolling any subject. Any untoward medical event will be classified as an AE, regardless of its causal 
relationship with the study. 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 DSMO, 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.  
 
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.  
 
The Data Safety Monitoring Officer (DSMO), Dr. Cheryl Laffer, Director of the Vanderbilt Hypertension 
Service, a patient-oriented investigator with experience in clinical research, will serve as DSMO and 
consultant for this grant. We will provide annual reports to the IRB and the DSMO regarding recruitment, 
safety reporting, data quality, and efficacy. 
 
Incidents of non-compliance with the protocol will be reported at the time of continuing review.  
 
8.0 
Study Withdrawal/Discontinuation 
 
Criteria for study withdrawal/discontinuation 
 


 
 
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• 
Drug-related toxicity 
• 
Requirement for prohibited concomitant medications (see exclusion criteria) 
• 
Pregnancy 
• 
Request by subject to terminate treatment 
• 
Clinical reasons believed to be life threatening by the physician, even if not addressed on the 
potential risk section 
 
9.0 
Statistical Considerations  
 Sample size justification: For aim 1, we will compare primary endpoint (OT) between each surgery group 
(RYGB and VSG) and the medical weight loss group. Based on the literature,22 we expect a 48.5% 
reduction in orthostatic tolerance (OT) after RYGB/VSG (normal baseline OT is 36.7±7.3 (mean±SD) 
versus poor OT 18.9±5.96.22) After weight loss, we estimated a ≈25% reduction in OT (baseline 36.7±7.3 
to 27.5 ±7). This is a 25% difference in OT between surgical versus medical weight loss. We need n=15 
per group to have 90% power to detect the difference between 18.9 and 27.5 using SD of 7 with type I 
error rate of 0.05. We plan to enroll 15 subjects in each of the 3 groups. For aim 2, in visit 3  we will 
randomize these 30 RYGB/VSG subjects with 1:1 ratio to the Strattera and placebo groups. We will 
compare OT between the placebo and the Strattera groups. We expect that OT is 18.9±5.96 (mean±SD) 
for the placebo group (similar to the surgery group in aim 1) and the Strattera group will improve by 
≈50% or 28.35±7 (mean±SD). With 15 in each group in aim 2, we will have excellent (96%) power to 
detect the difference.  
 
Data Analysis Plan: the primary analyses will focus on the comparison of the primary endpoint, OT. In 
aim 1 between RYGB vs. medical weight loss, and between VSG vs. medical weight loss; in aim 2: 
between Strattera versus placebo groups. Secondary endpoints include changes in hemodynamics (blood 
pressure, heart rate) during HUT and HUT+LBNP, orthostatic changes in plasma catecholamines, and 
MSNA. We will assess continuous outcomes for normality. If normality is violated, we will apply data 
transformation or non-parametric analysis methods. We will provide summary statistics for both 
numerical and categorical variables by study arms and assess comparability among randomization groups.  
In both aims, we will estimate the direct between-group difference by means with its 95% confidence 
interval (CI), which will be tested using either two-sample t-test or Wilcoxon Rank Sum test.  A 
multivariate general linear model will be used to evaluate the group or treatment effects while adjusting 
the baseline measure of the endpoint. Model over fitting will be avoided using the rule of thumb of 10 
observations per parameter in the model. Analyses of secondary endpoints and other exploratory analyses 
will be conducted similarly. We will test all hypothesis at the level of α=0.05. We will use SPSS for 
Windows (Version 22.0, SPSS, Chicago) and the open source statistical package R (version 3.4.3, R Core 
Team, 2017) for analyses (https://www.R-project.org.) 
 
 
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. Members of the research team will have access to 
the patient's medical record during the screening visit and 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 
 


 
 
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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).  
 
 
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