xml: <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/NCT05983744</url>
    </required_header>
    <id_info>
      <org_study_id>IRB #2019-046</org_study_id>
      <nct_id>NCT05983744</nct_id>
    </id_info>
    <brief_title>Pulsatile Perfusion Therapy Phase II</brief_title>
    <acronym>PPT2</acronym>
    <official_title>Pulsatile Perfusion Therapy Phase II: A Novel Approach for Improving Cerebral Tissue Blood Flow and Oxygenation</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Caroline Rickards</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of North Texas Health Science Center</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Individuals who suffer from a stroke, cardiac arrest, or traumatic bleeding (hemorrhage)&#xD;
        injuries often have compromised blood flow and oxygen to the brain which can lead to the&#xD;
        death of brain cells, and if the patient survives, subsequent difficulty in thinking and&#xD;
        performing tasks of daily living. Traditionally, delivery of a constant flow of blood to the&#xD;
        brain has been thought to be the most important factor for the survival of brain cells. In&#xD;
        this study, a novel intervention will be assessed called &quot;pulsatile perfusion therapy&quot;,&#xD;
        delivering blood flow in a slow pulsing pattern. It is anticipated this intervention will&#xD;
        improve brain blood flow and oxygenation during these serious clinical events.&#xD;
  &#xD;
        There is a specific interest in whether delivery of brain blood flow with a slow pulsatile&#xD;
        pattern will improve oxygenation of brain tissue, particularly when the brain is challenged&#xD;
        under low oxygen (hypoxia) and low volume (hypovolemia) conditions, simulating stroke,&#xD;
        cardiac arrest, and hemorrhage. A technique called oscillatory lower body negative pressure&#xD;
        (OLBNP) will be used in healthy human participants, facilitating delivery of blood flow to&#xD;
        the brain with different pulsing patterns. This technique will allow for determination of the&#xD;
        ideal pattern of brain blood flow that improves oxygenation of the brain tissue. Measurements&#xD;
        will be made of substances in the blood that may be released with pulsatile flow which act on&#xD;
        the blood vessels to increase flow and delivery of oxygen.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Hemorrhage due to trauma is one of the leading causes of morbidity and mortality worldwide in&#xD;
        both the civilian and military settings. A major factor contributing to death and disability&#xD;
        from severe blood loss is poor tissue perfusion and oxygenation of the vital organs.&#xD;
        Traditionally, protection of absolute cerebral blood flow (CBF) has been deemed the most&#xD;
        important factor in maintaining perfusion and oxygenation. In recent years, it has been shown&#xD;
        that low frequency (LF, ~0.1 Hz) pulsatile CBF is associated with increased tolerance to&#xD;
        simulated hemorrhage in healthy human subjects, despite ≥30% reductions in absolute CBF. The&#xD;
        underlying mechanism for this improvement in tolerance is unclear; the proposed study aims to&#xD;
        address this knowledge gap. The central hypothesis is that LF oscillations (~0.1 Hz) will&#xD;
        improve CBF and tissue oxygenation under hypoxic and/or hypovolemic conditions, due to&#xD;
        increased shear stress and the release of vasoactive mediators that facilitate vasodilation&#xD;
        and enhanced tissue perfusion. This hypothesis will be addressed in two Specific Aims under&#xD;
        hypoxic and hypovolemic conditions: 1) determine if inducing oscillations in arterial blood&#xD;
        pressure and CBF at 0.1 Hz elicits shear stress-induced vasodilation, subsequently increasing&#xD;
        CBF and oxygenation; and, 2) assess the effect of 0.1 Hz oscillations on the release of shear&#xD;
        stress-induced vasoactive mediators. Twenty human subjects (males and females) will be&#xD;
        recruited to address these aims using oscillatory lower body negative pressure (OLBNP) to&#xD;
        induce 0.1 Hz oscillations. Measurements will include CBF (intracranial &amp; extracranial&#xD;
        arteries), shear stress, cerebral oxygenation, arterial pressure, and venous blood samples&#xD;
        for assessment of nitric oxide, prostaglandin E2, 6-keto-PGF1α (a metabolite of prostacyclin,&#xD;
        PGI2), histamine, and endothelin-1. The rationale for the proposed research is to identify a&#xD;
        mechanism for the previously observed increase in tolerance to simulated hemorrhage with&#xD;
        increases in LF oscillations in arterial pressure and CBF. The approach is innovative as it&#xD;
        challenges the traditional association of hemodynamic variability with negative clinical&#xD;
        outcomes using a novel methodological approach in human subjects. This contribution is&#xD;
        significant as the findings may provide an alternative approach to maintaining cerebral&#xD;
        perfusion and oxygenation under conditions of hypovolemia and/or hypoxia.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Completed</overall_status>
    <start_date type="Actual">February 27, 2020</start_date>
    <completion_date type="Actual">December 17, 2021</completion_date>
    <primary_completion_date type="Actual">December 17, 2021</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Change in ScO2</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Cerebral tissue oxygen saturation</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in ICA flow</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Internal carotid artery blood flow</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in MCA velocity</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Middle cerebral artery velocity</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in circulating vasoactive mediators</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Venous plasma nitric oxide and endothelin</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Change in arterial pressure</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Systolic, diastolic, and mean arterial pressure</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in heart rate</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Heart rate</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in stroke volume</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Stroke volume</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in PCA velocity</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>Posterior cerebral artery velocity</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in etO2 and etCO2</measure>
      <time_frame>Up to 3-months</time_frame>
      <description>End-tidal oxygen and carbon dioxide</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Actual">21</enrollment>
    <condition>Hemorrhage</condition>
    <arm_group>
      <arm_group_label>Pulsatile perfusion therapy (PPT)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Application of oscillatory lower body negative pressure (LBNP) at specific target frequencies of interest.</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>0 Hz Control</intervention_name>
      <description>Lower body negative pressure (LBNP) applied to -60 mmHg for 10-min</description>
      <arm_group_label>Pulsatile perfusion therapy (PPT)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>0.1 Hz PPT</intervention_name>
      <description>Lower body negative pressure (LBNP) applied at a frequency of 0.1 Hz from -30 mmHg to -90 mmHg</description>
      <arm_group_label>Pulsatile perfusion therapy (PPT)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>0.05 Hz PPT</intervention_name>
      <description>Lower body negative pressure (LBNP) applied at a frequency of 0.05 Hz from -30 mmHg to -90 mmHg</description>
      <arm_group_label>Pulsatile perfusion therapy (PPT)</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Aged 18 to 40 years&#xD;
  &#xD;
            2. Non-tobacco/nicotine users (e.g., cigarettes (including electronic cigarettes),&#xD;
               chewing tobacco, nicotine gum or patches)&#xD;
  &#xD;
            3. Systolic arterial pressure &lt;140 mmHg; diastolic arterial pressure &lt;90 mmHg&#xD;
  &#xD;
            4. Normal 12-lead ECG (reviewed by a physician)&#xD;
  &#xD;
            5. Normal clinical results from a medical exam reviewed by a board certified physician&#xD;
               (e.g., General Health Questionnaire - see attached document)&#xD;
  &#xD;
            6. Easily visualized internal carotid and vertebral arteries (via Doppler ultrasound) for&#xD;
               accurate measurement of velocity and diameter.&#xD;
  &#xD;
            7. Body mass index (BMI) &lt;30 kg/m2 unless athletic/muscular build; calculation = body&#xD;
               weight (kg)/height (m2); this criteria is used to ensure subjects will fit inside the&#xD;
               LBNP chamber&#xD;
  &#xD;
            8. Females only: documentation of a negative pregnancy test prior to the familiarization&#xD;
               and experimental sessions&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Age &lt;18 or &gt;40 years&#xD;
  &#xD;
            2. Use of tobacco/nicotine within the last 6 months (e.g., cigarettes (including&#xD;
               electronic cigarettes), chewing tobacco, nicotine gum or patches)&#xD;
  &#xD;
            3. Body mass index (BMI) &gt;30 kg/m2 unless athletic/muscular build; calculation = body&#xD;
               weight (kg)/height (m2)&#xD;
  &#xD;
            4. Not abstaining from the following 24 hours prior to the experimental session:&#xD;
               exercise, alcoholic substances, prescription or non-prescription medications (unless&#xD;
               cleared by the medical screener), dietary supplements, herbal medications, caffeinated&#xD;
               substances (including coffee, tea (iced or hot), caffeinated energy drinks or sodas).&#xD;
  &#xD;
            5. Inability to visualize the internal carotid and vertebral arteries (via Doppler&#xD;
               ultrasound) for accurate measurement of velocity and diameter.&#xD;
  &#xD;
            6. Positive pregnancy test&#xD;
  &#xD;
            7. Post-menopausal females&#xD;
  &#xD;
            8. Females with an erratic/irregular menstrual cycle&#xD;
  &#xD;
            9. Use of prescription drugs, non-prescription drugs or herbal medicines known to alter&#xD;
               cardiovascular, autonomic, or cerebrovascular function unless cleared prior to the&#xD;
               study&#xD;
  &#xD;
           10. Use of anti-hypertensive medications&#xD;
  &#xD;
           11. Use of beta blockers&#xD;
  &#xD;
           12. Frequent use of bronchodilators (occasional use, i.e. seasonally, is allowable)&#xD;
  &#xD;
           13. Use of anti-coagulant therapy&#xD;
  &#xD;
           14. Use of non-contraceptive related hormone therapy&#xD;
  &#xD;
           15. Current or past history of hyperthyroidism, or other thyroid hormone-related disease&#xD;
  &#xD;
           16. Signs of cardiovascular abnormalities (e.g., resting systolic blood pressure &gt;140mmHg&#xD;
               or diastolic blood pressure &gt;90mmHg; abnormal 12-lead ECG)&#xD;
  &#xD;
           17. History of cerebrovascular abnormalities (e.g., prior stroke, transient ischemic&#xD;
               attacks, epilepsy)&#xD;
  &#xD;
           18. Known history of atherosclerosis of the carotid arteries (i.e., plaque formation)&#xD;
  &#xD;
           19. History of concussion and or other loss of consciousness within the preceding month&#xD;
  &#xD;
           20. Autonomic dysfunction (e.g., Shy-Drager Syndrome, Bradbury-Eggleston syndrome, sinus&#xD;
               arrhythmia, idiopathic orthostatic hypotension, fainting disorder)&#xD;
  &#xD;
           21. Respiratory illnesses (e.g., chronic asthma (including exercise-induced asthma),&#xD;
               Chronic Obstructive Pulmonary Disease, Reactive Airway Disease)&#xD;
  &#xD;
           22. History of anaphylaxis&#xD;
  &#xD;
           23. Known allergies to medications or other substances (e.g. latex) unless cleared prior&#xD;
               to the study&#xD;
  &#xD;
           24. History of pre-syncopal/syncopal episodes or orthostatic hypotension&#xD;
  &#xD;
           25. Donated blood within the last 60 days&#xD;
  &#xD;
           26. History or family history of abnormal blood clotting, clots in deep veins in the legs&#xD;
               or pelvis, or blood clots to the lungs aa) Known or suspected abdominal hernia bb)&#xD;
               History of alcohol or drug abuse which inhibits the subject's ability to complete this&#xD;
               study cc) Known depression, anxiety, or any other mental health issue which inhibits&#xD;
               the subject's ability to complete this study dd) Known claustrophobia ee) Previous&#xD;
               positive diagnosis of COVID-19&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>40 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>University of North Texas Health Science Center</name>
        <address>
          <city>Fort Worth</city>
          <state>Texas</state>
          <zip>76107</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>November 23, 2021</study_first_submitted>
    <study_first_submitted_qc>August 1, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 9, 2023</study_first_posted>
    <last_update_submitted>August 1, 2023</last_update_submitted>
    <last_update_submitted_qc>August 1, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 9, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>University of North Texas Health Science Center</investigator_affiliation>
      <investigator_full_name>Caroline Rickards</investigator_full_name>
      <investigator_title>Associate Professor</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hemorrhage</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>All IPD that underlie the results in a publication</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_time_frame>Starting 6 months after publication.</ipd_time_frame>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05983744
  org study id: IRB #2019-046
  nct id: NCT05983744
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Individuals who suffer from a stroke, cardiac arrest, or traumatic bleeding (hemorrhage)
        injuries often have compromised blood flow and oxygen to the brain which can lead to the
        death of brain cells, and if the patient survives, subsequent difficulty in thinking and
        performing tasks of daily living. Traditionally, delivery of a constant flow of blood to the
        brain has been thought to be the most important factor for the survival of brain cells. In
        this study, a novel intervention will be assessed called "pulsatile perfusion therapy",
        delivering blood flow in a slow pulsing pattern. It is anticipated this intervention will
        improve brain blood flow and oxygenation during these serious clinical events.
  
        There is a specific interest in whether delivery of brain blood flow with a slow pulsatile
        pattern will improve oxygenation of brain tissue, particularly when the brain is challenged
        under low oxygen (hypoxia) and low volume (hypovolemia) conditions, simulating stroke,
        cardiac arrest, and hemorrhage. A technique called oscillatory lower body negative pressure
        (OLBNP) will be used in healthy human participants, facilitating delivery of blood flow to
        the brain with different pulsing patterns. This technique will allow for determination of the
        ideal pattern of brain blood flow that improves oxygenation of the brain tissue. Measurements
        will be made of substances in the blood that may be released with pulsatile flow which act on
        the blood vessels to increase flow and delivery of oxygen.
  Hemorrhage due to trauma is one of the leading causes of morbidity and mortality worldwide in
        both the civilian and military settings. A major factor contributing to death and disability
        from severe blood loss is poor tissue perfusion and oxygenation of the vital organs.
        Traditionally, protection of absolute cerebral blood flow (CBF) has been deemed the most
        important factor in maintaining perfusion and oxygenation. In recent years, it has been shown
        that low frequency (LF, ~0.1 Hz) pulsatile CBF is associated with increased tolerance to
        simulated hemorrhage in healthy human subjects, despite ≥30% reductions in absolute CBF. The
        underlying mechanism for this improvement in tolerance is unclear; the proposed study aims to
        address this knowledge gap. The central hypothesis is that LF oscillations (~0.1 Hz) will
        improve CBF and tissue oxygenation under hypoxic and/or hypovolemic conditions, due to
        increased shear stress and the release of vasoactive mediators that facilitate vasodilation
        and enhanced tissue perfusion. This hypothesis will be addressed in two Specific Aims under
        hypoxic and hypovolemic conditions: 1) determine if inducing oscillations in arterial blood
        pressure and CBF at 0.1 Hz elicits shear stress-induced vasodilation, subsequently increasing
        CBF and oxygenation; and, 2) assess the effect of 0.1 Hz oscillations on the release of shear
        stress-induced vasoactive mediators. Twenty human subjects (males and females) will be
        recruited to address these aims using oscillatory lower body negative pressure (OLBNP) to
        induce 0.1 Hz oscillations. Measurements will include CBF (intracranial & extracranial
        arteries), shear stress, cerebral oxygenation, arterial pressure, and venous blood samples
        for assessment of nitric oxide, prostaglandin E2, 6-keto-PGF1α (a metabolite of prostacyclin,
        PGI2), histamine, and endothelin-1. The rationale for the proposed research is to identify a
        mechanism for the previously observed increase in tolerance to simulated hemorrhage with
        increases in LF oscillations in arterial pressure and CBF. The approach is innovative as it
        challenges the traditional association of hemodynamic variability with negative clinical
        outcomes using a novel methodological approach in human subjects. This contribution is
        significant as the findings may provide an alternative approach to maintaining cerebral
        perfusion and oxygenation under conditions of hypovolemia and/or hypoxia.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Basic Science
  masking: None (Open Label)
  measure: Change in ScO2
  time frame: Up to 3-months
  description: Cerebral tissue oxygen saturation
  measure: Change in ICA flow
  time frame: Up to 3-months
  description: Internal carotid artery blood flow
  measure: Change in MCA velocity
  time frame: Up to 3-months
  description: Middle cerebral artery velocity
  measure: Change in circulating vasoactive mediators
  time frame: Up to 3-months
  description: Venous plasma nitric oxide and endothelin
  measure: Change in arterial pressure
  time frame: Up to 3-months
  description: Systolic, diastolic, and mean arterial pressure
  measure: Change in heart rate
  time frame: Up to 3-months
  description: Heart rate
  measure: Change in stroke volume
  time frame: Up to 3-months
  description: Stroke volume
  measure: Change in PCA velocity
  time frame: Up to 3-months
  description: Posterior cerebral artery velocity
  measure: Change in etO2 and etCO2
  time frame: Up to 3-months
  description: End-tidal oxygen and carbon dioxide
  arm group label: Pulsatile perfusion therapy (PPT)
  arm group type: Experimental
  description: Application of oscillatory lower body negative pressure (LBNP) at specific target frequencies of interest.
  intervention type: Other
  intervention name: 0 Hz Control
  description: Lower body negative pressure (LBNP) applied to -60 mmHg for 10-min
  arm group label: Pulsatile perfusion therapy (PPT)
  intervention type: Other
  intervention name: 0.1 Hz PPT
  description: Lower body negative pressure (LBNP) applied at a frequency of 0.1 Hz from -30 mmHg to -90 mmHg
  arm group label: Pulsatile perfusion therapy (PPT)
  intervention type: Other
  intervention name: 0.05 Hz PPT
  description: Lower body negative pressure (LBNP) applied at a frequency of 0.05 Hz from -30 mmHg to -90 mmHg
  arm group label: Pulsatile perfusion therapy (PPT)
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 40 Years
  healthy volunteers: Accepts Healthy Volunteers
  facility: 
  country: United States
  responsible party type: Sponsor-Investigator
  investigator affiliation: University of North Texas Health Science Center
  investigator full name: Caroline Rickards
  investigator title: Associate Professor
  mesh term: Hemorrhage
  sharing ipd: Yes
  ipd description: All IPD that underlie the results in a publication
  ipd info type: Study Protocol
  ipd time frame: Starting 6 months after publication.