Orthostatic Intolerance After Bariatric Surgery (RYGB)

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.

Study Overview

• Status: Terminated
• Conditions: Orthostatic Intolerance
• Intervention / Treatment: Drug: Placebo; Drug: Atomoxetine

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37027
      • Cyndya Shibao

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months	To assess the hemodynamic (Blood Pressure) changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.	0- 3 months
Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months	To assess the hemodynamic (cardiac output [CO]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.	0- 3 months
Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months	To assess the hemodynamic (stroke volume [SV]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.	0- 3 months
Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months	To assess the hemodynamic ( total peripheral resistance [TPR]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope	0- 3 months

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

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Cyndya Shiabao, M.D., Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): May 31, 2021
• Study Completion (Actual): May 31, 2021

Study Registration Dates

• First Submitted: January 16, 2019
• First Submitted That Met QC Criteria: January 16, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Actual): September 27, 2024
• Last Update Submitted That Met QC Criteria: June 10, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Autonomic Nervous System Diseases; Primary Dysautonomias; Orthostatic Intolerance; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Uptake Inhibitors; Atomoxetine Hydrochloride
• Other Study ID Numbers: 180499

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No