<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03808740</url>
  </required_header>
  <id_info>
    <org_study_id>180499</org_study_id>
    <nct_id>NCT03808740</nct_id>
  </id_info>
  <brief_title>Orthostatic Intolerance After Bariatric Surgery</brief_title>
  <acronym>RYGB</acronym>
  <official_title>Orthostatic Intolerance After Bariatric Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      More than 78 million adults in the U.S. are obese. Bariatric surgery is the only modality&#xD;
      that results in sustained weight loss along with reversal of diabetes mellitus, and a&#xD;
      decrease in cardiovascular events. Obesity is associated with increased sympathetic nervous&#xD;
      system (SNS) activity that contributes to blood pressure regulation; sympathetic&#xD;
      vasoconstrictor activity is maximally activated upon standing and is fundamental for the&#xD;
      maintenance of orthostatic tolerance. After bariatric surgery, there is a significant and&#xD;
      sustained reduction in SNS activity at three and six months after the procedure, which is&#xD;
      related to weight loss. Recently, multiple retrospective studies have reported an orthostatic&#xD;
      intolerance (OI) syndrome after bariatric surgery characterized by chronic pre-syncopal&#xD;
      symptoms, syncope and orthostatic hypotension. In the Vanderbilt University Medical Center&#xD;
      bariatric surgical center, 741 post-bariatric surgery patients reported OI symptoms, 98&#xD;
      (13.2%) of these patients, progressed to chronic OI and in17 cases, the OI was so disabling&#xD;
      that patients initiated treatment with pressor agents. More than 50% of OI cases in the&#xD;
      cohort developed the condition during a weight-stable period. Hence, investigators propose&#xD;
      the novel hypothesis that after bariatric surgery, the persistent reduction in SNS activity&#xD;
      contributes to impaired orthostatic tolerance, which is independent of weight loss.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Considering that SNS vasoconstrictor activity depends on synaptic norepinephrine&#xD;
      concentrations, investigators propose a proof-of-concept study to test the hypothesis that&#xD;
      the norepinephrine transporter (NET) inhibitor, atomoxetine, which increases synaptic&#xD;
      norepinephrine concentrations, will improve post-bariatric OI. Understanding the changes in&#xD;
      SNS activity and its contribution to orthostatic tolerance after bariatric surgery is of&#xD;
      utmost importance to unravel the mechanisms of a novel and unrecognized syndrome,&#xD;
      post-bariatric OI. In 2014, nearly 200,000 individuals in the US underwent bariatric surgery,&#xD;
      and the number of bariatric surgery procedures is expected to increase by 22% each year. It&#xD;
      is projected, therefore, an increase in the incidence of post-bariatric OI.&#xD;
&#xD;
      Participants with Roux-en-Y gastric bypass (RYGB) and Vertical sleeve gastrectomy (VSG) will&#xD;
      be studied.&#xD;
&#xD;
      OI is a chronic and disabling condition; treatment is challenging because current therapies&#xD;
      have debatable efficacy.&#xD;
&#xD;
      The proposed application will not only provide central knowledge on the pathophysiology of&#xD;
      this new syndrome but also will fill an unmet therapeutic need by repurposing NET inhibitors&#xD;
      for the treatment of OI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2018</start_date>
  <completion_date type="Actual">May 31, 2021</completion_date>
  <primary_completion_date type="Actual">May 31, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Orthostatic Tolerance</measure>
    <time_frame>about 1 hour</time_frame>
    <description>the time between the start of the 60 degree head up tilt until pre-syncope&#xD;
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) &lt;80 or SBP&gt;90 and pre-syncopal symptoms (nausea, lightheadedness, dizziness)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Norepinephrine transporter Inhibition</measure>
    <time_frame>baseline and 30 minutes</time_frame>
    <description>the ratio of dihydroxyphenylglycol (DHPG) to Norepinephrine is used as the biomarker for NET inhibition</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Orthostatic Intolerance</condition>
  <arm_group>
    <arm_group_label>Roux-en-Y gastric bypass (RYGB)/Atomoxetine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with standard of care RYGB will receive atomoxetine, 0.5 mg/kg/day for 3 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vertical sleeve gastrectomy (VSG) /Atomoxetine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with standard of care VSG will receive atomoxetine 0.5 mg/kg/day for 3 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Roux-en-Y gastric bypass (RYGB)/Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants with standard of care RYGB will receive placebo 0.5 mg/kg/day for 3 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vertical sleeve gastrectomy (VSG)/ Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants with standard of care VSG will receive placebo 0.5 mg/kg/day for 3 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atomoxetine</intervention_name>
    <description>atomoxetine 0.5 mg/kg/day.</description>
    <arm_group_label>Roux-en-Y gastric bypass (RYGB)/Atomoxetine</arm_group_label>
    <arm_group_label>Vertical sleeve gastrectomy (VSG) /Atomoxetine</arm_group_label>
    <other_name>strattera</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>sugar pill</description>
    <arm_group_label>Roux-en-Y gastric bypass (RYGB)/Placebo</arm_group_label>
    <arm_group_label>Vertical sleeve gastrectomy (VSG)/ Placebo</arm_group_label>
    <other_name>sugar pill</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Obese subjects that will undergo bariatric surgery or medical weight loss.&#xD;
&#xD;
          -  Age 18-60 years&#xD;
&#xD;
          -  BMI &gt;35 kg/m2&#xD;
&#xD;
          -  Weight &lt; 400 lbs&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diabetes type 1&#xD;
&#xD;
          -  Use of an alpha blockers, clonidine, beta-blockers.&#xD;
&#xD;
          -  Pregnancy or breast-feeding. Women of childbearing potential will be required to have&#xD;
             undergone tubal ligation or to be using an oral contraceptive or barrier methods of&#xD;
             birth control.&#xD;
&#xD;
          -  The use of any strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine,&#xD;
             tipranavir).&#xD;
&#xD;
          -  Use of selective NET inhibitors.&#xD;
&#xD;
          -  Use of monoamine oxidase inhibitors.&#xD;
&#xD;
          -  Cardiovascular disease such as myocardial infarction within six months prior to the&#xD;
             study, presence of angina pectoris, significant arrhythmia, congestive heart failure&#xD;
             (left ventricular hypertrophy acceptable), deep vein thrombosis, pulmonary embolism,&#xD;
             second or third degree heart block, mitral valve stenosis, aortic stenosis or&#xD;
             hypertrophic cardiomyopathy&#xD;
&#xD;
          -  History of serious neurologic disease such as cerebral hemorrhage, stroke, or&#xD;
             transient ischemic attack&#xD;
&#xD;
          -  Hematocrit &lt; 34%&#xD;
&#xD;
          -  Any underlying or acute disease requiring regular medication which could possibly pose&#xD;
             a threat to the subject or make implementation of the protocol or interpretation of&#xD;
             the study results difficult&#xD;
&#xD;
          -  Mental conditions rendering a subject unable to understand the nature, scope and&#xD;
             possible consequences of the study&#xD;
&#xD;
          -  Inability to comply with the protocol, e.g., uncooperative attitude, inability to&#xD;
             return for follow-up visits, unlikelihood of completing the study, and investigator&#xD;
             discretion&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cyndya Shiabao, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cyndya Shibao</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>January 16, 2019</study_first_submitted>
  <study_first_submitted_qc>January 16, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>March 1, 2022</last_update_submitted>
  <last_update_submitted_qc>March 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Cyndya Shibao, MD</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Orthostatic Intolerance</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atomoxetine Hydrochloride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 13, 2022</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03808740
org study id: 180499
nct id: NCT03808740
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Orthostatic Tolerance
time frame: about 1 hour
description: 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)
measure: Norepinephrine transporter Inhibition
time frame: baseline and 30 minutes
description: the ratio of dihydroxyphenylglycol (DHPG) to Norepinephrine is used as the biomarker for NET inhibition
arm group label: Roux-en-Y gastric bypass (RYGB)/Atomoxetine
arm group type: Experimental
description: Participants with standard of care RYGB will receive atomoxetine, 0.5 mg/kg/day for 3 days
arm group label: Vertical sleeve gastrectomy (VSG) /Atomoxetine
arm group type: Experimental
description: Participants with standard of care VSG will receive atomoxetine 0.5 mg/kg/day for 3 days
arm group label: Roux-en-Y gastric bypass (RYGB)/Placebo
arm group type: Placebo Comparator
description: Participants with standard of care RYGB will receive placebo 0.5 mg/kg/day for 3 days
arm group label: Vertical sleeve gastrectomy (VSG)/ Placebo
arm group type: Placebo Comparator
description: Participants with standard of care VSG will receive placebo 0.5 mg/kg/day for 3 days
intervention type: Drug
intervention name: Atomoxetine
description: atomoxetine 0.5 mg/kg/day.
arm group label: Roux-en-Y gastric bypass (RYGB)/Atomoxetine
arm group label: Vertical sleeve gastrectomy (VSG) /Atomoxetine
other name: strattera
intervention type: Drug
intervention name: Placebo
description: sugar pill
arm group label: Roux-en-Y gastric bypass (RYGB)/Placebo
arm group label: Vertical sleeve gastrectomy (VSG)/ Placebo
other name: sugar pill
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Cyndya Shiabao, M.D.
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Cyndya Shibao, MD
investigator title: Assistant Professor of Medicine
mesh term: Orthostatic Intolerance
mesh term: Atomoxetine Hydrochloride
sharing ipd: No
submitted: December 13, 2022