<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/NCT02990078</url>
  </required_header>
  <id_info>
    <org_study_id>825942</org_study_id>
    <nct_id>NCT02990078</nct_id>
  </id_info>
  <brief_title>Non-invasive Measurement of Cerebrovascular Reactivity After Traumatic Brain Injury</brief_title>
  <official_title>Cerebrovascular Reactivity Assessed With Functional Near-infrared Spectroscopy as a Biomarker of Traumatic Microvascular Injury After Moderate-severe Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators will longitudinally measure cerebrovascular reactivity (CVR) by functional&#xD;
      near-infrared spectroscopy (fNIRS) in acute (≤3 days from injury), subacute, and chronic&#xD;
      phases after TBI as a biomarker of TCVI as compared to healthy controls. CVR will be measured&#xD;
      by fNIRS response to hypercapnia. The investigators hypothesize that CVR will be decreased&#xD;
      after TBI and that these decreases will correlate with clinical outcomes. Furthermore, the&#xD;
      investigators predict that administration of a vasodilatory medication (sildenafil) will&#xD;
      augment CVR after TBI.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sufficient sample size enrolled to demonstrate scientific goals of the study&#xD;
  </why_stopped>
  <start_date type="Actual">December 2016</start_date>
  <completion_date type="Actual">September 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in CVR prior to sildenafil administration</measure>
    <time_frame>&lt; 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change CVR after sildenafil administration</measure>
    <time_frame>&lt;72 hours, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship of CVR with symptom reports, as measured by the Neurobehavioral Symptom Inventory (NBSI).</measure>
    <time_frame>&lt; 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">26</enrollment>
  <condition>TBI</condition>
  <arm_group>
    <arm_group_label>Acute TBI</arm_group_label>
    <description>Subjects will be recruited from the neurointensive care unit within 72 hours of their injury. At the time of informed consent, the investigators will perform fNIRS testing with a hypercapnia challenge, fNIRS with hypercapnia challenge 60 minutes after a single oral dose of 50mg sildenafil citrate, outcome qustionaires and symptom checklists (including: Glasgow Outcomes Scale-Extended, Rivermead Post-Concussive Symptom Questionnaire, Brief Symptom Inventory, Alcohol Consumption Questionnaire, Patient Health Questionnaire, and Insomnia Severity Index). This will all be administered again at 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, and 4 years after injury.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-acute/Chronic TBI</arm_group_label>
    <description>Subjects who suffered a TBI previously and have now entered a subacute or chronic phase of their TBI will be approached by the research team at their clinic visit with a TBI specialist. In those subjects, study timing will be based on the time of their original injury, therefore will start study visits at the next possible time point.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <description>The investigators will also enroll healthy &quot;peer controls&quot;. These control subjects will be family members and friends of TBI subjects. These peer controls are likely to have similar environmental and socioeconomic exposures/support which may impact recovery after TBI and may also impact CVR. These control subjects will meet the same inclusion/exclusion criteria as TBI subjects without the requirement for an injury or acute brain imaging. These subjects will be tested in the same way as both TBI groups, but will only have one visit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sildenafil citrate</intervention_name>
    <description>Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study.</description>
    <arm_group_label>Acute TBI</arm_group_label>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>Sub-acute/Chronic TBI</arm_group_label>
    <other_name>Viagra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Functional Near Infared Spectroscopy</intervention_name>
    <description>Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes.</description>
    <arm_group_label>Acute TBI</arm_group_label>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>Sub-acute/Chronic TBI</arm_group_label>
    <other_name>fNIRS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Hypercapnia Challenge</intervention_name>
    <description>The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.</description>
    <arm_group_label>Acute TBI</arm_group_label>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>Sub-acute/Chronic TBI</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Male and female, aged 18 or older, presenting with a diagnosis of traumatic brain injury&#xD;
        (TBI) and healthy peer control volunteers .&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women, aged ≥18&#xD;
&#xD;
          2. CT evidence of TBI-linked abnormality&#xD;
&#xD;
               -  Traumatic subarachnoid hemorrhage&#xD;
&#xD;
               -  Intracerebral hemorrhage/contusion&#xD;
&#xD;
               -  Subdural/epidural hematoma&#xD;
&#xD;
          3. Ability to undergo fNIRS testing with hypercapnia challenge&#xD;
&#xD;
          4. Subject able to provide informed consent&#xD;
&#xD;
          5. Attending of record agrees to include subject in study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unstable respiratory or hemodynamic status&#xD;
&#xD;
          2. Evidence of penetrating brain injury&#xD;
&#xD;
          3. TBI requiring craniotomy or craniectomy&#xD;
&#xD;
          4. Evidence or risk of ICP crisis&#xD;
&#xD;
          5. History of disabling pre-existing neurologic disorder (e.g. dementia, uncontrolled&#xD;
             epilepsy, multiple sclerosis, strokes, brain tumors, prior severe TBI, or other&#xD;
             disorder that confounds interpretation of NIRS testing or neuropsychological results)&#xD;
&#xD;
          6. History of pre-existing disabling mental illness (e.g. major depression or&#xD;
             schizophrenia)&#xD;
&#xD;
          7. Exclusion criteria for sildenafil administration:&#xD;
&#xD;
               -  History of melanoma&#xD;
&#xD;
               -  current use of organic nitrate vasodilators&#xD;
&#xD;
               -  current use of ritonavir (HIV-protease inhibitor)&#xD;
&#xD;
               -  current use of erythromycin, ketoconazole, or itraconazole; current use of&#xD;
                  cimetidine&#xD;
&#xD;
               -  current use of alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax),&#xD;
                  and terazosin (Hytrin) prazosin (Minipres)&#xD;
&#xD;
               -  resting hypotension (systolic BP &lt;90)&#xD;
&#xD;
               -  severe renal insufficiency&#xD;
&#xD;
               -  hepatic cirrhosis&#xD;
&#xD;
               -  acute ischemic stroke within past 2 months&#xD;
&#xD;
               -  acute myocardial infarction within past 2 months&#xD;
&#xD;
               -  unstable angina pectoris&#xD;
&#xD;
               -  acute or chronic heart failure&#xD;
&#xD;
               -  retinitis pigmentosa&#xD;
&#xD;
               -  pregnant or breastfeeding female&#xD;
&#xD;
               -  known hypersensitivity or allergy to sildenafil&#xD;
&#xD;
          8. Unstable cardiac status that constitutes a contraindication to sexual activity&#xD;
&#xD;
          9. Inability to read and communicate in English (necessary to obtain reliable&#xD;
             neuropsychometric data)&#xD;
&#xD;
         10. Nursing mothers&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ramon Diaz-Arrastia, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania Perelman School of Medicine, Department of Neurology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Penn Presbyterian Medical Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>December 5, 2016</study_first_submitted>
  <study_first_submitted_qc>December 7, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <last_update_submitted>October 10, 2022</last_update_submitted>
  <last_update_submitted_qc>October 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pennsylvania</investigator_affiliation>
    <investigator_full_name>Ramon Diaz-Arrastia</investigator_full_name>
    <investigator_title>Presidential Professor</investigator_title>
  </responsible_party>
  <keyword>TBI</keyword>
  <keyword>CVR</keyword>
  <keyword>Hypercapnia</keyword>
  <keyword>fNIRS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sildenafil Citrate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02990078
org study id: 825942
nct id: NCT02990078
lead sponsor: 
has dmc: No
The investigators will longitudinally measure cerebrovascular reactivity (CVR) by functional
      near-infrared spectroscopy (fNIRS) in acute (≤3 days from injury), subacute, and chronic
      phases after TBI as a biomarker of TCVI as compared to healthy controls. CVR will be measured
      by fNIRS response to hypercapnia. The investigators hypothesize that CVR will be decreased
      after TBI and that these decreases will correlate with clinical outcomes. Furthermore, the
      investigators predict that administration of a vasodilatory medication (sildenafil) will
      augment CVR after TBI.
observational model: Cohort
time perspective: Prospective
measure: Change in CVR prior to sildenafil administration
time frame: < 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years
measure: Change CVR after sildenafil administration
time frame: <72 hours, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years
measure: Relationship of CVR with symptom reports, as measured by the Neurobehavioral Symptom Inventory (NBSI).
time frame: < 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years
arm group label: Acute TBI
description: Subjects will be recruited from the neurointensive care unit within 72 hours of their injury. At the time of informed consent, the investigators will perform fNIRS testing with a hypercapnia challenge, fNIRS with hypercapnia challenge 60 minutes after a single oral dose of 50mg sildenafil citrate, outcome qustionaires and symptom checklists (including: Glasgow Outcomes Scale-Extended, Rivermead Post-Concussive Symptom Questionnaire, Brief Symptom Inventory, Alcohol Consumption Questionnaire, Patient Health Questionnaire, and Insomnia Severity Index). This will all be administered again at 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, and 4 years after injury.
arm group label: Sub-acute/Chronic TBI
description: Subjects who suffered a TBI previously and have now entered a subacute or chronic phase of their TBI will be approached by the research team at their clinic visit with a TBI specialist. In those subjects, study timing will be based on the time of their original injury, therefore will start study visits at the next possible time point.
arm group label: Healthy Controls
description: The investigators will also enroll healthy "peer controls". These control subjects will be family members and friends of TBI subjects. These peer controls are likely to have similar environmental and socioeconomic exposures/support which may impact recovery after TBI and may also impact CVR. These control subjects will meet the same inclusion/exclusion criteria as TBI subjects without the requirement for an injury or acute brain imaging. These subjects will be tested in the same way as both TBI groups, but will only have one visit.
intervention type: Drug
intervention name: Sildenafil citrate
description: Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study.
arm group label: Acute TBI
arm group label: Healthy Controls
arm group label: Sub-acute/Chronic TBI
other name: Viagra
intervention type: Device
intervention name: Functional Near Infared Spectroscopy
description: Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes.
arm group label: Acute TBI
arm group label: Healthy Controls
arm group label: Sub-acute/Chronic TBI
other name: fNIRS
intervention type: Other
intervention name: Hypercapnia Challenge
description: The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.
arm group label: Acute TBI
arm group label: Healthy Controls
arm group label: Sub-acute/Chronic TBI
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Ramon Diaz-Arrastia, MD, PhD
role: Principal Investigator
affiliation: University of Pennsylvania Perelman School of Medicine, Department of Neurology
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Pennsylvania
investigator full name: Ramon Diaz-Arrastia
investigator title: Presidential Professor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Sildenafil Citrate
sharing ipd: No