Brief Title
Orthostatic Intolerance After Bariatric Surgery
Official Title
Orthostatic Intolerance After Bariatric Surgery
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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Orthostatic Tolerance
Secondary Outcome
Norepinephrine transporter Inhibition
Condition
Orthostatic Intolerance
Intervention
Atomoxetine
Study Arms / Comparison Groups
Roux-en-Y gastric bypass (RYGB)/Atomoxetine
Description: Participants with standard of care RYGB will receive atomoxetine, 0.5 mg/kg/day for 3 days
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
16
Start Date
July 1, 2018
Completion Date
May 31, 2021
Primary Completion Date
May 31, 2021
Eligibility Criteria
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
Gender
All
Ages
18 Years - 60 Years
Accepts Healthy Volunteers
No
Contacts
Cyndya Shiabao, M.D., ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT03808740
Organization ID
180499
Responsible Party
Principal Investigator
Study Sponsor
Vanderbilt University Medical Center
Study Sponsor
Cyndya Shiabao, M.D., Principal Investigator, Vanderbilt University Medical Center
Verification Date
March 2022