Orthostatic Intolerance After Bariatric Surgery

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