<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/NCT03261570</url>
  </required_header>
  <id_info>
    <org_study_id>1R01HL134674-01A1</org_study_id>
    <nct_id>NCT03261570</nct_id>
  </id_info>
  <brief_title>Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in POTS</brief_title>
  <official_title>Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in Postural Tachycardia Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>New York Medical College</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>New York Medical College</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance&#xD;
      associated with excessive upright tachycardia, and occurs predominantly in young females&#xD;
      (&gt;85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory&#xD;
      often called &quot;brain fog&quot; by patients. Task-related neurovascular coupling (NVC) links neural&#xD;
      activity to an increase in CBF known as &quot;functional hyperemia&quot;. Although memory task&#xD;
      performance and NVC deteriorated with angle of tilt in POTS but not healthy controls,&#xD;
      cerebral blood flow (CBF) remained similar to control. Instead, the investigators observed&#xD;
      extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained&#xD;
      and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused&#xD;
      impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples&#xD;
      BP to HR to buffer BP changes. The investigators hypothesize that the cardiovagal baroreflex&#xD;
      becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and&#xD;
      accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF&#xD;
      and Brain Fog in POTS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Orthostatic intolerance is defined by debilitating upright symptoms that are relieved by&#xD;
      sitting or lying. Symptoms include upright lightheadedness, fatigue, confusion, and decreased&#xD;
      memory called 'Brain Fog' by patients. The most common chronic form is Postural Tachycardia&#xD;
      Syndrome (POTS), characterized by excessive upright tachycardia without hypotension. Of note,&#xD;
      &gt;85% of POTS patients are female. The proposal that Brain Fog was caused by reduced cerebral&#xD;
      blood flow (CBF) has been disproven, because graded incremental upright tilt failed to&#xD;
      demonstrate difference in mean CBF compared to healthy volunteers. Nevertheless, memory task&#xD;
      performance deteriorates with angle of tilt as does task-related neurovascular coupling&#xD;
      (NVC), which links neural activity to an increase in CBF known as &quot;functional hyperemia&quot;. The&#xD;
      investigators have previously observed that large low frequency (0.07-0.13 Hz) oscillations&#xD;
      in BP (OBP), which entrained and amplified oscillations in CBF (OCBF), increased with tilt&#xD;
      angle and were associated with impaired working memory and reduced functional hyperemia.&#xD;
&#xD;
      The sympathetic baroreflex remains intact and HR is excessively increased in the absence of&#xD;
      parasympathetic counterregulation. The cardiovagal baroreflex couples BP to HR to buffer BP&#xD;
      changes. Large low frequency BP oscillations, representing a resonance within the sympathetic&#xD;
      baroreflex loop, occur if there is central hypovolemia, an intact sympathetic baroreflex, and&#xD;
      reduced parasympathetic buffering of BP by HR; conditions found in upright POTS. This leads&#xD;
      to the following hypothetical paradigm:&#xD;
&#xD;
      ↓Cardiovagal Baroreflex → ↑OBP → ↑↑OCBF → ↓NVC → ↓working memory. Therefore, in this&#xD;
      application, the investigators hypothesize that the cardiovagal baroreflex is impaired in&#xD;
      POTS while supine, becomes further impaired with orthostasis, and accounts for OBP, OCBF, and&#xD;
      loss of NVC. Further, the investigators propose that improving the cardiovagal baroreflex&#xD;
      improves hemodynamics and Brain Fog in POTS patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2017</start_date>
  <completion_date type="Actual">June 1, 2022</completion_date>
  <primary_completion_date type="Actual">June 1, 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cardiovagal Baroreflex during orthostatic stress</measure>
    <time_frame>1 year</time_frame>
    <description>Cardiovagal Baroreflex during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. The unmedicated baroreflex measurement will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Baroreflex measurements will be obtained using the standard &quot;modified Oxford&quot; technique.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cognitive ability during orthostatic stress</measure>
    <time_frame>1 year</time_frame>
    <description>. Cognitive ability during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. Cognitive ability will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Cognitive ability will be assessed with a standard 2-Back test in which patients identify identical alphabetic characters appearing 2 characters before the current displayed character in a sequence of 29 characters.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cardiac output measure by inert gas breathing technique</measure>
    <time_frame>1 year</time_frame>
    <description>Cardiac output measure by inert gas breathing technique. Cardiac output is the amount of blood pumped by the heart in one minute. The technique uses the Innocor system in which the relative levels of two inert gases - one blood soluble and one insoluble component - are measured over a few respirations (about 5 breaths or 15 seconds). The rate of disappearance of the soluble gas from the alveolar space is proportional to the flow of blood perfusing the lungs and equals the cardiac output.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the cardiac cycle</measure>
    <time_frame>1 year</time_frame>
    <description>Arterial blood pressure in mmHg over each cardiac cycle will be collected using finger photoplethysmography. The arterial pressure is reported as an aggregate of 3 extracted quantities: the systolic blood pressure which is the maximum blood pressure over a cardiac cycle; the diastolic blood pressure which is the minimum blood pressure over a cardiac cycle; and the mean blood pressure which is the average blood pressure over a cardiac cycle.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">51</enrollment>
  <condition>Postural Orthostatic Tachycardia Syndrome (POTS)</condition>
  <condition>POTS</condition>
  <condition>Orthostatic Intolerance</condition>
  <arm_group>
    <arm_group_label>Pyridostigmine and Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Digoxin and Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyridostigmine</intervention_name>
    <description>60mg by mouth</description>
    <arm_group_label>Pyridostigmine and Placebo</arm_group_label>
    <other_name>Mestinon</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Digoxin</intervention_name>
    <description>0.5 (500mcg) by mouth</description>
    <arm_group_label>Digoxin and Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Lactulose 50mg by mouth</description>
    <arm_group_label>Digoxin and Placebo</arm_group_label>
    <arm_group_label>Pyridostigmine and Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for POTS patients:&#xD;
&#xD;
        POTS patients referred for day to day orthostatic intolerance with greater than 3 symptoms&#xD;
        for greater than 3 months and will have the diagnosis of symptomatic postural tachycardia&#xD;
        made during a screening tilt table test :&#xD;
&#xD;
          -  dizziness&#xD;
&#xD;
          -  nausea and vomiting&#xD;
&#xD;
          -  palpitations&#xD;
&#xD;
          -  fatigue&#xD;
&#xD;
          -  headache&#xD;
&#xD;
          -  exercise intolerance&#xD;
&#xD;
          -  blurred vision&#xD;
&#xD;
          -  abnormal sweating heat.&#xD;
&#xD;
        Healthy control subjects:&#xD;
&#xD;
          -  normal physical examination, and normal electrocardiographic and echocardiographic&#xD;
             evaluations.&#xD;
&#xD;
          -  Only those free from heart disease, and from systemic illness will be eligible to&#xD;
             participate.&#xD;
&#xD;
          -  This excludes patients with illnesses and disease states known to be associated with&#xD;
             endothelial cell dysfunction such as diabetes, renal disease, congestive heart&#xD;
             failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm,&#xD;
             immune mediated disease, trauma, morbid obesity and peripheral vascular disease.&#xD;
&#xD;
        At the time of testing all patients and control subjects must refrain from vasoactive drugs&#xD;
        for two weeks.&#xD;
&#xD;
        Exclusion Criteria for both POTS and healthy controls:&#xD;
&#xD;
          -  An active medical condition that may explain the diagnosis&#xD;
&#xD;
          -  A previous medical condition with undocumented resolution that may explain the&#xD;
             diagnosis&#xD;
&#xD;
          -  any systemic or overt structural, arrhythmic or myopathic cardiovascular disease&#xD;
&#xD;
          -  any illnesses known to produce autonomic dysfunction such as diabetes, heart disease,&#xD;
             renal disease, systemic hypertension, acute and chronic inflammatory diseases,&#xD;
             neoplastic disease, immune mediated disease, major trauma and burns, morbid obesity&#xD;
             and peripheral vascular disease will also be excluded.&#xD;
&#xD;
          -  Cigarette smokers will be excluded.&#xD;
&#xD;
          -  Past or present major psychiatric disorder&#xD;
&#xD;
          -  Substance abuse within 2 years before onset of symptoms.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Julian M. Stewart, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>New York Medical College</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>New York Medical College/Bradhurst building</name>
      <address>
        <city>Hawthorne</city>
        <state>New York</state>
        <zip>10532</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>August 14, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>September 27, 2022</last_update_submitted>
  <last_update_submitted_qc>September 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>New York Medical College</investigator_affiliation>
    <investigator_full_name>Julian Stewart</investigator_full_name>
    <investigator_title>Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>Postural Orthostatic Tachycardia Syndrome (POTS)</keyword>
  <keyword>POTS</keyword>
  <keyword>Orthostatic Intolerance</keyword>
  <keyword>Digoxin</keyword>
  <keyword>Pyridostigmine</keyword>
  <keyword>Mestinon</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Postural Orthostatic Tachycardia Syndrome</mesh_term>
    <mesh_term>Orthostatic Intolerance</mesh_term>
    <mesh_term>Tachycardia</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Digoxin</mesh_term>
    <mesh_term>Pyridostigmine Bromide</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03261570
org study id: 1R01HL134674-01A1
nct id: NCT03261570
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance
      associated with excessive upright tachycardia, and occurs predominantly in young females
      (>85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory
      often called "brain fog" by patients. Task-related neurovascular coupling (NVC) links neural
      activity to an increase in CBF known as "functional hyperemia". Although memory task
      performance and NVC deteriorated with angle of tilt in POTS but not healthy controls,
      cerebral blood flow (CBF) remained similar to control. Instead, the investigators observed
      extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained
      and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused
      impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples
      BP to HR to buffer BP changes. The investigators hypothesize that the cardiovagal baroreflex
      becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and
      accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF
      and Brain Fog in POTS.
Orthostatic intolerance is defined by debilitating upright symptoms that are relieved by
      sitting or lying. Symptoms include upright lightheadedness, fatigue, confusion, and decreased
      memory called 'Brain Fog' by patients. The most common chronic form is Postural Tachycardia
      Syndrome (POTS), characterized by excessive upright tachycardia without hypotension. Of note,
      >85% of POTS patients are female. The proposal that Brain Fog was caused by reduced cerebral
      blood flow (CBF) has been disproven, because graded incremental upright tilt failed to
      demonstrate difference in mean CBF compared to healthy volunteers. Nevertheless, memory task
      performance deteriorates with angle of tilt as does task-related neurovascular coupling
      (NVC), which links neural activity to an increase in CBF known as "functional hyperemia". The
      investigators have previously observed that large low frequency (0.07-0.13 Hz) oscillations
      in BP (OBP), which entrained and amplified oscillations in CBF (OCBF), increased with tilt
      angle and were associated with impaired working memory and reduced functional hyperemia.

      The sympathetic baroreflex remains intact and HR is excessively increased in the absence of
      parasympathetic counterregulation. The cardiovagal baroreflex couples BP to HR to buffer BP
      changes. Large low frequency BP oscillations, representing a resonance within the sympathetic
      baroreflex loop, occur if there is central hypovolemia, an intact sympathetic baroreflex, and
      reduced parasympathetic buffering of BP by HR; conditions found in upright POTS. This leads
      to the following hypothetical paradigm:

      ↓Cardiovagal Baroreflex → ↑OBP → ↑↑OCBF → ↓NVC → ↓working memory. Therefore, in this
      application, the investigators hypothesize that the cardiovagal baroreflex is impaired in
      POTS while supine, becomes further impaired with orthostasis, and accounts for OBP, OCBF, and
      loss of NVC. Further, the investigators propose that improving the cardiovagal baroreflex
      improves hemodynamics and Brain Fog in POTS patients.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Diagnostic
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Cardiovagal Baroreflex during orthostatic stress
time frame: 1 year
description: Cardiovagal Baroreflex during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. The unmedicated baroreflex measurement will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Baroreflex measurements will be obtained using the standard "modified Oxford" technique.
measure: Cognitive ability during orthostatic stress
time frame: 1 year
description: . Cognitive ability during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. Cognitive ability will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Cognitive ability will be assessed with a standard 2-Back test in which patients identify identical alphabetic characters appearing 2 characters before the current displayed character in a sequence of 29 characters.
measure: Cardiac output measure by inert gas breathing technique
time frame: 1 year
description: Cardiac output measure by inert gas breathing technique. Cardiac output is the amount of blood pumped by the heart in one minute. The technique uses the Innocor system in which the relative levels of two inert gases - one blood soluble and one insoluble component - are measured over a few respirations (about 5 breaths or 15 seconds). The rate of disappearance of the soluble gas from the alveolar space is proportional to the flow of blood perfusing the lungs and equals the cardiac output.
measure: Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the cardiac cycle
time frame: 1 year
description: Arterial blood pressure in mmHg over each cardiac cycle will be collected using finger photoplethysmography. The arterial pressure is reported as an aggregate of 3 extracted quantities: the systolic blood pressure which is the maximum blood pressure over a cardiac cycle; the diastolic blood pressure which is the minimum blood pressure over a cardiac cycle; and the mean blood pressure which is the average blood pressure over a cardiac cycle.
measure: Heart rate
time frame: 1 year
measure: systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output
time frame: 1 year
arm group label: Pyridostigmine and Placebo
arm group type: Active Comparator
description: Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day
arm group label: Digoxin and Placebo
arm group type: Active Comparator
description: Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day
intervention type: Drug
intervention name: Pyridostigmine
description: 60mg by mouth
arm group label: Pyridostigmine and Placebo
other name: Mestinon
intervention type: Drug
intervention name: Digoxin
description: 0.5 (500mcg) by mouth
arm group label: Digoxin and Placebo
intervention type: Drug
intervention name: Placebo
description: Lactulose 50mg by mouth
arm group label: Digoxin and Placebo
arm group label: Pyridostigmine and Placebo
criteria: 
gender: Female
minimum age: 15 Years
maximum age: 30 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Julian M. Stewart, M.D., Ph.D.
role: Principal Investigator
affiliation: New York Medical College
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: New York Medical College
investigator full name: Julian Stewart
investigator title: Professor of Pediatrics
mesh term: Postural Orthostatic Tachycardia Syndrome
mesh term: Orthostatic Intolerance
mesh term: Tachycardia
mesh term: Syndrome
mesh term: Digoxin
mesh term: Pyridostigmine Bromide