Orthostatic Intolerance After Bariatric Surgery

Study Overview
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Brief Summary
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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
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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.

Official Title
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Orthostatic Intolerance After Bariatric Surgery

Conditions
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Orthostatic Intolerance

Intervention / Treatment
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* Drug: Atomoxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obese subjects that will undergo bariatric surgery or medical weight loss. Age 18-60 years BMI >35 kg/m2 Weight < 400 lbs Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Roux-en-Y gastric bypass (RYGB)/Atomoxetine<br>Participants with standard of care RYGB will receive atomoxetine, 0.5 mg/kg/day for 3 days | Drug: Atomoxetine<br>* atomoxetine 0.5 mg/kg/day.<br>* Other names: strattera;|
| Experimental: Vertical sleeve gastrectomy (VSG) /Atomoxetine<br>Participants with standard of care VSG will receive atomoxetine 0.5 mg/kg/day for 3 days | Drug: Atomoxetine<br>* atomoxetine 0.5 mg/kg/day.<br>* Other names: strattera;|
| Placebo Comparator: Roux-en-Y gastric bypass (RYGB)/Placebo<br>Participants with standard of care RYGB will receive placebo 0.5 mg/kg/day for 3 days | Drug: Placebo<br>* sugar pill<br>* Other names: sugar pill;|
| Placebo Comparator: Vertical sleeve gastrectomy (VSG)/ Placebo<br>Participants with standard of care VSG will receive placebo 0.5 mg/kg/day for 3 days | Drug: Placebo<br>* sugar pill<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Orthostatic Tolerance | the time between the start of the 60 degree head up tilt until pre-syncope Participant will be placed in 60degree head-up tilt (HUT) for 30 min following by lower body negative pressure in escalating negative pressures (-20, -40, -60 mm Hg) until pre-syncope (defined as systolic BP (SBP, mm Hg) <80 or SBP>90 and pre-syncopal symptoms (nausea, lightheadedness, dizziness) | about 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Norepinephrine transporter Inhibition | the ratio of dihydroxyphenylglycol (DHPG) to Norepinephrine is used as the biomarker for NET inhibition | baseline and 30 minutes |