<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/NCT02995837</url>
  </required_header>
  <id_info>
    <org_study_id>16-012750</org_study_id>
    <secondary_id>K01HL130719</secondary_id>
    <nct_id>NCT02995837</nct_id>
  </id_info>
  <brief_title>CBF and Childhood OSAS</brief_title>
  <official_title>Cerebral Blood Flow and Neurocognition in Children With Obstructive Sleep Apnea</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital of Philadelphia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital of Philadelphia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Obstructive sleep apnea syndrome (OSAS) causes hypoxemia and hypercapnia, which may impair&#xD;
      cerebral blood flow and cause deficits in behavior. This is a case-control study designed to&#xD;
      investigate cerebral blood flow and neurocognitive function in children with OSAS when&#xD;
      compared to these findings from normal children. The study hypothesis is that children with&#xD;
      OSAS have an impaired cerebral blood flow during wakefulness and sleep compared to normal&#xD;
      controls, and that the degree of this impairment correlates with neurocognitive function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OSAS is characterized by repetitive occlusion of the upper airway during sleep that results&#xD;
      in hypoxemia, hypercapnia and arousal from sleep. Children with the obstructive sleep apnea&#xD;
      syndrome (OSAS) have impaired behavior and cognition compared to normal controls. Previous&#xD;
      studies in adults with OSAS have shown significant alterations of cerebral blood flow during&#xD;
      wakefulness and sleep and our preliminary data showed blunted cerebral blood flow response to&#xD;
      hypercapnia in children with OSAS during wakefulness. However, it is unknown whether children&#xD;
      with OSAS also have impaired cerebral blood flow during sleep. It is also unknown whether the&#xD;
      deficits in behavior and cognition in children are associated with cerebral blood flow&#xD;
      dysregulation.&#xD;
&#xD;
      This study will investigate whether the changes in cerebral blood flow during wakefulness and&#xD;
      sleep elicited by hypercapneic challenge, differ in children with OSAS compared to normal&#xD;
      controls. Additionally the study will evaluate the changes in cerebral blood flow during&#xD;
      wakefulness and sleep elicited by hypercapneic challenge in children with OSAS before and&#xD;
      after treatment (adenotonsillectomy, adenoidectomy, or tonsillectomy). Finally, the study&#xD;
      will investigate whether the changes in cerebral blood flow elicited by the aforementioned&#xD;
      testing correlate with neurocognitive outcomes.&#xD;
&#xD;
      Children with OSAS aged 6-12 years will be recruited following a clinical polysomnogram.&#xD;
      Normal age- and gender-matched controls will be recruited from the general community.&#xD;
&#xD;
      The primary interventions of this study for the two groups (OSAS and controls) are: sleep&#xD;
      studies, neurocognitive testing, measurement of cerebral blood flow by near-infrared&#xD;
      spectroscopy during hypercapnic challenges conducted during wakefulness and sleep. In&#xD;
      addition, OSAS subjects will be re-tested after clinical treatment of OSAS to evaluate for&#xD;
      resolution of OSAS, and all subjects will be re-tested at two separate time points after&#xD;
      baseline to compare changes due to the treatment of OSAS versus those occurring secondary to&#xD;
      normal development.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2016</start_date>
  <completion_date type="Actual">January 1, 2022</completion_date>
  <primary_completion_date type="Actual">January 1, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in cerebral blood flow (CBF) at baseline between OSAS and controls</measure>
    <time_frame>Up to 24 hours</time_frame>
    <description>To determine whether children with OSAS have impaired blood flow regulation elicited by hypercapneic challenge compared to normal controls.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Comparison of the change in CBF from baseline to study completion between OSAS and control subjects</measure>
    <time_frame>Up to 12 Months</time_frame>
    <description>The change in CBF measurements obtained at baseline when compared at 6 and 12 months after baseline for controls and after adenotonsillectomy for OSAS subjects.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Determine the association between CBF regulation and severity of OSAS</measure>
    <time_frame>Up to 12 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Determine the association between cognitive and behavioral measurements and severity of OSAS</measure>
    <time_frame>Up to 12 months</time_frame>
  </other_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">48</enrollment>
  <condition>Obstructive Sleep Apnea Syndrome</condition>
  <arm_group>
    <arm_group_label>Obstructive Sleep Apnea Syndrome (OSAS)</arm_group_label>
    <description>The study duration is estimated at 12-14 months approximately. However, this will depend on the timing of treatment as they will undergo testing pre- and post-OSAS treatment. Participation will entail a total of 8 visits including:&#xD;
Pre-treatment - neurocognitive testing, and CBF during wakefulness testing duration is one full day. The CBF nighttime testing is one full night.&#xD;
Post-treatment - Six to twelve weeks after clinically indicated surgical treatment, OSAS participants will have a repeat baseline polysomnogram (one full night) to assess for residual OSA. Six and twelve months after the surgical treatment, the sleep study with the nighttime CBF testing, as well as the daytime neurocognitive testing and CBF testing will be repeated to assess for changes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <description>The study will include 7 total visits for controls: a baseline sleep study to ensure normalcy, three full days of neurocognitive testing and CBF testing (baseline, 6 and 12 months), and three sleep studies with CBF testing (baseline, 6 and 12 months). A daytime visit and one night time visit may be scheduled during a 24-hour period if the participant and family wish so. Otherwise, they will be scheduled on separate days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Sleep Study</intervention_name>
    <description>Overnight, video-recorded sleep study will be performed in a dedicated pediatric sleep lab. Sleep architecture, apneas and hypopneas, arterial oxygen saturation and end-tidal carbon dioxide tension will be evaluated during the sleep study. Safety measures including arterial oxygen saturation using pulse oximetry, EEG and EKG will be continuously monitored during the study.</description>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>Obstructive Sleep Apnea Syndrome (OSAS)</arm_group_label>
    <other_name>Polysomnography</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Neurocognitive Testing</intervention_name>
    <description>Cognitive and behavioral measures including intelligence, attention, working memory, and processing speed will be assessed by a trained psychologist.</description>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>Obstructive Sleep Apnea Syndrome (OSAS)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>CBF During Wakefulness</intervention_name>
    <description>Cerebral blood flow (CBF) will be measure using Diffuse optical and correlation spectroscopy (DOS/DCS), a non-significant risk device used to collect data for this study but not being tested as part of the protocol. Light sources and detectors which are embedded in a rubber pad will be attached to the subject's head in order to record right and left hemispheric cerebral blood flow, total hemoglobin concentration and tissue oxygen saturation. Measurements will be continuously recorded during the study and averaged for purposes of statistical analysis. With DOS/DCS in place, ventilatory response to hypercapnia will be determined using the rebreathing technique, a standard clinical test. While CBF is being measured, subjects will wear nose clips and sit comfortably breathing through a mouthpiece while the level of carbon dioxide is adjusted over a 3-4 minute period. Oxygen and carbon dioxide levels will be carefully monitored throughout the testing.</description>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>Obstructive Sleep Apnea Syndrome (OSAS)</arm_group_label>
    <other_name>Cerebral Blood Flow Testing During Hypercapneic Ventilatory Response (Daytime/Wakefulness)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>CBF During Sleep</intervention_name>
    <description>This is the same as the CBF testing during wakefulness/daytime except that it will be done during a sleep study performed with a continuous positive airway pressure (CPAP) mask not nose clips and a mouthpiece. With DOS/DCS in place, ventilatory response to hypercapnia will be determined using the rebreathing technique. While CBF is being measured, OSAS subjects will receive an individualized positive pressure aimed at treating obstructive sleep apnea and controls will receive a standard pressure. End-tidal carbon dioxide will be measured via a port in the mask. A constant flow of carbon dioxide will be introduced to the circuit, a slowly adjusted until the patient arouses or for a maximum of 3 minutes, whichever occurs first. One trial will be attempted in each sleep stage (slow-wave sleep and rapid-eye-movement) with a minimum of 15 minute of breathing room air between challenges. Oxygen and carbon dioxide levels will be carefully monitored throughout the testing.</description>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>Obstructive Sleep Apnea Syndrome (OSAS)</arm_group_label>
    <other_name>Cerebral Blood Flow Testing During Hypercapneic Ventilatory Response (Nighttime/Sleep)</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Children with OSAS aged 6-12 years will be recruited following a clinical polysomnogram.&#xD;
        Normal age- and gender- matched controls will be recruited from the general community.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria (OSAS subjects):&#xD;
&#xD;
          1. Age between 6 years and 12 years. The lower limit criterion was selected to include&#xD;
             children who can understand and cooperate with testing. The upper limit criterion was&#xD;
             selected to avoid overlap with the adult presentation of OSAS.&#xD;
&#xD;
          2. Absence of neurologic, cardiovascular, pulmonary, or any other chronic illness with&#xD;
             the exception of well-controlled asthma&#xD;
&#xD;
          3. No prior surgery on the nose, palate or oropharynx including an adenotonsillectomy&#xD;
&#xD;
          4. No current drug intake that may interfere with testing such as sedatives or stimulants&#xD;
&#xD;
          5. No prior treatment of sleep-disordered breathing&#xD;
&#xD;
          6. Polysomnographic recording criteria: subjects with OSAS must have an obstructive apnea&#xD;
             hypopnea index (AHI) ≥ 5/hour and be a candidate for clinically-indicated surgical&#xD;
             treatment.&#xD;
&#xD;
          7. Parental/guardian permission (informed consent) and if appropriate, child assent.&#xD;
&#xD;
        Exclusion Criteria (OSAS Subjects)&#xD;
&#xD;
          1. Previous adenotonsillectomy&#xD;
&#xD;
          2. Previous use of CPAP&#xD;
&#xD;
          3. Craniofacial anomalies that can interfere with upper airway anatomy (e.g.,&#xD;
             Treacher-Collins syndrome)&#xD;
&#xD;
          4. Genetic syndromes (e.g., Trisomy 21, Prader-Willi)&#xD;
&#xD;
          5. Attention deficit hyperactivity disorder (ADHD) on medication&#xD;
&#xD;
          6. Developmental delay&#xD;
&#xD;
          7. Non-English speaking participants due to the nature of neurobehavioral testing&#xD;
&#xD;
        Inclusion Criteria (Control subjects)&#xD;
&#xD;
          1. Age between 6 years and 12 years. The lower limit criterion was selected to include&#xD;
             children who can understand and cooperate with testing. The upper limit criterion was&#xD;
             selected to avoid overlap with the adult presentation of OSAS.&#xD;
&#xD;
          2. Absence of neurologic, cardiovascular, pulmonary, or any other chronic illness with&#xD;
             the exception of well-controlled asthma&#xD;
&#xD;
          3. No prior surgery on the nose, palate or oropharynx including an adenotonsillectomy&#xD;
&#xD;
          4. No current drug intake that may interfere with testing such as sedatives or stimulants&#xD;
&#xD;
          5. No prior treatment of sleep-disordered breathing&#xD;
&#xD;
          6. Polysomnographic recording criteria: Normal control subjects must have an AHI ≤&#xD;
             1.5/hour.&#xD;
&#xD;
          7. Parental/guardian permission (informed consent) and if appropriate, child assent.&#xD;
&#xD;
        Exclusion Criteria (Control Subjects)&#xD;
&#xD;
          1. Previous adenotonsillectomy&#xD;
&#xD;
          2. Previous use of CPAP&#xD;
&#xD;
          3. Craniofacial anomalies that can interfere with upper airway anatomy (e.g.,&#xD;
             Treacher-Collins syndrome)&#xD;
&#xD;
          4. Genetic syndromes (e.g., Trisomy 21, Prader-Willi)&#xD;
&#xD;
          5. ADHD on medication&#xD;
&#xD;
          6. Developmental delay&#xD;
&#xD;
          7. Positive Pediatric Sleep Questionnaire&#xD;
&#xD;
          8. Non-English speaking participants due to the nature of neurobehavioral testing&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>12 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ignacio E. Tapia, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital of Philadelphia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</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>April 2023</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 14, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 16, 2016</study_first_posted>
  <last_update_submitted>April 27, 2023</last_update_submitted>
  <last_update_submitted_qc>April 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Obstructive Sleep Apnea Syndrome</keyword>
  <keyword>Cerebral Blood Flow</keyword>
  <keyword>Neurocognition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apnea</mesh_term>
    <mesh_term>Sleep Apnea Syndromes</mesh_term>
    <mesh_term>Sleep Apnea, Obstructive</mesh_term>
  </condition_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/NCT02995837
org study id: 16-012750
secondary id: K01HL130719
nct id: NCT02995837
lead sponsor: 
collaborator: 
has dmc: Yes
Obstructive sleep apnea syndrome (OSAS) causes hypoxemia and hypercapnia, which may impair
      cerebral blood flow and cause deficits in behavior. This is a case-control study designed to
      investigate cerebral blood flow and neurocognitive function in children with OSAS when
      compared to these findings from normal children. The study hypothesis is that children with
      OSAS have an impaired cerebral blood flow during wakefulness and sleep compared to normal
      controls, and that the degree of this impairment correlates with neurocognitive function.
OSAS is characterized by repetitive occlusion of the upper airway during sleep that results
      in hypoxemia, hypercapnia and arousal from sleep. Children with the obstructive sleep apnea
      syndrome (OSAS) have impaired behavior and cognition compared to normal controls. Previous
      studies in adults with OSAS have shown significant alterations of cerebral blood flow during
      wakefulness and sleep and our preliminary data showed blunted cerebral blood flow response to
      hypercapnia in children with OSAS during wakefulness. However, it is unknown whether children
      with OSAS also have impaired cerebral blood flow during sleep. It is also unknown whether the
      deficits in behavior and cognition in children are associated with cerebral blood flow
      dysregulation.

      This study will investigate whether the changes in cerebral blood flow during wakefulness and
      sleep elicited by hypercapneic challenge, differ in children with OSAS compared to normal
      controls. Additionally the study will evaluate the changes in cerebral blood flow during
      wakefulness and sleep elicited by hypercapneic challenge in children with OSAS before and
      after treatment (adenotonsillectomy, adenoidectomy, or tonsillectomy). Finally, the study
      will investigate whether the changes in cerebral blood flow elicited by the aforementioned
      testing correlate with neurocognitive outcomes.

      Children with OSAS aged 6-12 years will be recruited following a clinical polysomnogram.
      Normal age- and gender-matched controls will be recruited from the general community.

      The primary interventions of this study for the two groups (OSAS and controls) are: sleep
      studies, neurocognitive testing, measurement of cerebral blood flow by near-infrared
      spectroscopy during hypercapnic challenges conducted during wakefulness and sleep. In
      addition, OSAS subjects will be re-tested after clinical treatment of OSAS to evaluate for
      resolution of OSAS, and all subjects will be re-tested at two separate time points after
      baseline to compare changes due to the treatment of OSAS versus those occurring secondary to
      normal development.
observational model: Case-Control
time perspective: Prospective
measure: Difference in cerebral blood flow (CBF) at baseline between OSAS and controls
time frame: Up to 24 hours
description: To determine whether children with OSAS have impaired blood flow regulation elicited by hypercapneic challenge compared to normal controls.
measure: Comparison of the change in CBF from baseline to study completion between OSAS and control subjects
time frame: Up to 12 Months
description: The change in CBF measurements obtained at baseline when compared at 6 and 12 months after baseline for controls and after adenotonsillectomy for OSAS subjects.
measure: Determine the association between CBF regulation and severity of OSAS
time frame: Up to 12 months
measure: Determine the association between cognitive and behavioral measurements and severity of OSAS
time frame: Up to 12 months
arm group label: Obstructive Sleep Apnea Syndrome (OSAS)
description: The study duration is estimated at 12-14 months approximately. However, this will depend on the timing of treatment as they will undergo testing pre- and post-OSAS treatment. Participation will entail a total of 8 visits including:
Pre-treatment - neurocognitive testing, and CBF during wakefulness testing duration is one full day. The CBF nighttime testing is one full night.
Post-treatment - Six to twelve weeks after clinically indicated surgical treatment, OSAS participants will have a repeat baseline polysomnogram (one full night) to assess for residual OSA. Six and twelve months after the surgical treatment, the sleep study with the nighttime CBF testing, as well as the daytime neurocognitive testing and CBF testing will be repeated to assess for changes.
arm group label: Controls
description: The study will include 7 total visits for controls: a baseline sleep study to ensure normalcy, three full days of neurocognitive testing and CBF testing (baseline, 6 and 12 months), and three sleep studies with CBF testing (baseline, 6 and 12 months). A daytime visit and one night time visit may be scheduled during a 24-hour period if the participant and family wish so. Otherwise, they will be scheduled on separate days.
intervention type: Other
intervention name: Sleep Study
description: Overnight, video-recorded sleep study will be performed in a dedicated pediatric sleep lab. Sleep architecture, apneas and hypopneas, arterial oxygen saturation and end-tidal carbon dioxide tension will be evaluated during the sleep study. Safety measures including arterial oxygen saturation using pulse oximetry, EEG and EKG will be continuously monitored during the study.
arm group label: Controls
arm group label: Obstructive Sleep Apnea Syndrome (OSAS)
other name: Polysomnography
intervention type: Other
intervention name: Neurocognitive Testing
description: Cognitive and behavioral measures including intelligence, attention, working memory, and processing speed will be assessed by a trained psychologist.
arm group label: Controls
arm group label: Obstructive Sleep Apnea Syndrome (OSAS)
intervention type: Other
intervention name: CBF During Wakefulness
description: Cerebral blood flow (CBF) will be measure using Diffuse optical and correlation spectroscopy (DOS/DCS), a non-significant risk device used to collect data for this study but not being tested as part of the protocol. Light sources and detectors which are embedded in a rubber pad will be attached to the subject's head in order to record right and left hemispheric cerebral blood flow, total hemoglobin concentration and tissue oxygen saturation. Measurements will be continuously recorded during the study and averaged for purposes of statistical analysis. With DOS/DCS in place, ventilatory response to hypercapnia will be determined using the rebreathing technique, a standard clinical test. While CBF is being measured, subjects will wear nose clips and sit comfortably breathing through a mouthpiece while the level of carbon dioxide is adjusted over a 3-4 minute period. Oxygen and carbon dioxide levels will be carefully monitored throughout the testing.
arm group label: Controls
arm group label: Obstructive Sleep Apnea Syndrome (OSAS)
other name: Cerebral Blood Flow Testing During Hypercapneic Ventilatory Response (Daytime/Wakefulness)
intervention type: Other
intervention name: CBF During Sleep
description: This is the same as the CBF testing during wakefulness/daytime except that it will be done during a sleep study performed with a continuous positive airway pressure (CPAP) mask not nose clips and a mouthpiece. With DOS/DCS in place, ventilatory response to hypercapnia will be determined using the rebreathing technique. While CBF is being measured, OSAS subjects will receive an individualized positive pressure aimed at treating obstructive sleep apnea and controls will receive a standard pressure. End-tidal carbon dioxide will be measured via a port in the mask. A constant flow of carbon dioxide will be introduced to the circuit, a slowly adjusted until the patient arouses or for a maximum of 3 minutes, whichever occurs first. One trial will be attempted in each sleep stage (slow-wave sleep and rapid-eye-movement) with a minimum of 15 minute of breathing room air between challenges. Oxygen and carbon dioxide levels will be carefully monitored throughout the testing.
arm group label: Controls
arm group label: Obstructive Sleep Apnea Syndrome (OSAS)
other name: Cerebral Blood Flow Testing During Hypercapneic Ventilatory Response (Nighttime/Sleep)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 6 Years
maximum age: 12 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ignacio E. Tapia, MD, MS
role: Principal Investigator
affiliation: Children's Hospital of Philadelphia
facility: 
country: United States
responsible party type: Sponsor
mesh term: Apnea
mesh term: Sleep Apnea Syndromes
mesh term: Sleep Apnea, Obstructive
sharing ipd: No