<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/NCT04403165</url>
  </required_header>
  <id_info>
    <org_study_id>20-00002</org_study_id>
    <secondary_id>1R21AG067549-01</secondary_id>
    <nct_id>NCT04403165</nct_id>
  </id_info>
  <brief_title>Locus-coeruleus Function in Normal Elderly and AD Risk</brief_title>
  <acronym>LEAD</acronym>
  <official_title>Locus-coeruleus Function in Normal Elderly and AD Risk</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NYU Langone Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>NYU Langone Health</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Growing evidence suggests that Alzheimer's disease (AD) pathological changes begin decades&#xD;
      before clinical symptoms and tau abnormalities in the locus coeruleus (LC) can be observed&#xD;
      since midlife. We have previously demonstrated functional vulnerability of the LC to aging&#xD;
      and stress, as well as an association between higher CSF tau and impaired sleep phenomena&#xD;
      influenced by the LC. We now aim to test whether LC dysfunction can be measured in&#xD;
      preclinical AD stages by LC targeted imaging, and whether it objectively affects sleep&#xD;
      architecture and attention. We will test this hypothesis in 30 cognitively normal older&#xD;
      adults by performing a full clinical evaluation, one night of polysomnography, a lumbar&#xD;
      puncture to obtain cerebrospinal fluid, [11C]MRB PET-MR, and attention testing. This study&#xD;
      has the potential to identify a new mechanism by which tau pathology contributes to sleep and&#xD;
      attention dysfunction and may provide a new therapeutic target for AD prevention.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is three-fold: to test whether lower NET availability in the LC is&#xD;
      associated with: first, CSF tau levels typical of preclinical stages of AD (Aim 1); second,&#xD;
      reduced REM and spindle density (Aim 2); and third, impaired performance on attention tasks&#xD;
      (Aim 3). The goal is to test the overarching hypothesis that LC dysfunction occurs in&#xD;
      preclinical AD stages, can be measured with MRB-PET, and translates into impairment of sleep&#xD;
      architecture (LC tonic dysfunction) and attention (LC phasic dysfunction).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 6, 2020</start_date>
  <completion_date type="Anticipated">August 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2024</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>Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values</measure>
    <time_frame>Visit 4 (1-4 weeks after LP)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Total REM Duration (Min)</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Time Spent in REM Sleep</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>REM Sleep Continuity</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
    <description>Reported as percentage of REM runs that are less than 5, greater than or equal to 5 and greater than or equal to 10 minutes).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>N2 Spindle Density</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean Psychomotor Vigilance Test (PVT) Reaction Time</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
    <description>PVT measures the reaction speed to a randomly time-occuring visual stimuli, allowing the assessment of several aspects of attention including response times, attention lapses and false starts.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean Oddball Test Response Time</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
    <description>The OddBall test measures task-related attention. Two different visual stimuli (frequent and infrequent) are presented in random succession as the subject presses a button only when the infrequent stimuli appears.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Correct Responses</measure>
    <time_frame>Visit 3 (1-4 weeks after Visit 2)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Levels of Hyperphosphorylated Tau (P-Tau, T-Tau)</measure>
    <time_frame>Visit 4 (1-4 weeks after LP)</time_frame>
    <description>Levels will be derived from the CSF and reported in pg/mL</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Aβ42/Aβ40 Ratio</measure>
    <time_frame>Visit 4 (1-4 weeks after LP)</time_frame>
    <description>The presence of amyloid plaques will be represented as the binary indicator of a CSF Aβ42/Aβ40 ratio</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>Cognitively Normal (CN) Older Adults</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Nocturnal polysomnography (NPSG)</intervention_name>
    <description>Nocturnal polysomnography (NPSG) to measure REM sleep and sleep spindles characteristics.</description>
    <arm_group_label>Cognitively Normal (CN) Older Adults</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Lumbar Puncture (LP)</intervention_name>
    <description>Lumbar puncture (LP) to measure CSF P-Tau, T-Tau and Aβ42/40 ratio.</description>
    <arm_group_label>Cognitively Normal (CN) Older Adults</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB)</intervention_name>
    <description>PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]O-methylreboxetine ([11C]MRB) to measure NET availability.</description>
    <arm_group_label>Cognitively Normal (CN) Older Adults</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Psychomotor Vigilance Task (PVT)</intervention_name>
    <description>Psychomotor vigilance task (PVT) and the OddBall to measure test taskattention performance.</description>
    <arm_group_label>Cognitively Normal (CN) Older Adults</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  Male and female subjects with normal cognition and 60-75 years of age will be&#xD;
             enrolled.&#xD;
&#xD;
          -  Subjects will be within normal limits on neurological and psychiatric examinations.&#xD;
             All subjects enrolled will have both a Clinical Dementia Rating (CDR)=0 and a MMSE&gt;27.&#xD;
&#xD;
          -  All subjects will have had a minimum of 12 years of education. Among underrepresented&#xD;
             group (URG) subjects, &gt;80% of the elderly individuals coming to the NYU-ADRC meet this&#xD;
             criterion. (The education restriction reduces performance variance on cognitive test&#xD;
             measures and improves the sensitivity for detecting pathology and disease progression&#xD;
             using the robust norms available at the NYU ADRC. Given the majority of subjects will&#xD;
             meet this criterion we do not consider this a major selection bias or generalization&#xD;
             limitation for this study).&#xD;
&#xD;
          -  An informed family member or life-partner (preferably bed-partner) will be interviewed&#xD;
             to confirm the reliability of the subject interview.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of brain tumor, MRI evidence of brain damage or brain disease including&#xD;
             significant trauma, hydrocephalus, seizures, mental retardation or other serious&#xD;
             neurological disorder (e.g. Parkinson's disease or other movement disorders). Subjects&#xD;
             with a Fazekas scale &gt;2 will be excluded.&#xD;
&#xD;
          -  Significant history of alcoholism or drug abuse.&#xD;
&#xD;
          -  History of psychiatric illness (e.g., schizophrenia, bipolar, PTSD, or life-long&#xD;
             history of major depression).&#xD;
&#xD;
          -  Geriatric Depression Scale (short form)&gt;5.&#xD;
&#xD;
          -  Insulin dependent diabetes.&#xD;
&#xD;
          -  Evidence of clinically relevant cardiac, pulmonary, endocrine or hematological&#xD;
             conditions.&#xD;
&#xD;
          -  Physical impairment of such severity as to adversely affect the validity of&#xD;
             psychological testing.&#xD;
&#xD;
          -  Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard&#xD;
             for MRI imaging.&#xD;
&#xD;
          -  History of a first-degree family member with early onset (age &lt;60 years) dementia.&#xD;
&#xD;
          -  Irregular sleep-wake rhythms (based on the actigraphy recordings) or significant OSA&#xD;
             (AHI3a%&gt;/=15).&#xD;
&#xD;
          -  Medications affecting cognition or sleep.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ricardo Osorio</last_name>
    <role>Principal Investigator</role>
    <affiliation>NYU Langone Health</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dishari Azad</last_name>
    <phone>646-754-2229</phone>
    <email>Dishari.azad@nyulangone.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ricardo Osorio</last_name>
    <phone>212-263-3255</phone>
    <email>ricardo.osorio@nyulangone.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>NYU Grossman School of Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Icahn School of Medicine Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 21, 2020</study_first_submitted>
  <study_first_submitted_qc>May 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>May 10, 2023</last_update_submitted>
  <last_update_submitted_qc>May 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Norepinephrine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All of the individual participant data collected during the trial, after deidentification.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Immediately following publication. No end date.</ipd_time_frame>
    <ipd_access_criteria>The investigator who proposed to use the ricardo.osorio@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.</ipd_access_criteria>
  </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/NCT04403165
org study id: 20-00002
secondary id: 1R21AG067549-01
nct id: NCT04403165
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Growing evidence suggests that Alzheimer's disease (AD) pathological changes begin decades
      before clinical symptoms and tau abnormalities in the locus coeruleus (LC) can be observed
      since midlife. We have previously demonstrated functional vulnerability of the LC to aging
      and stress, as well as an association between higher CSF tau and impaired sleep phenomena
      influenced by the LC. We now aim to test whether LC dysfunction can be measured in
      preclinical AD stages by LC targeted imaging, and whether it objectively affects sleep
      architecture and attention. We will test this hypothesis in 30 cognitively normal older
      adults by performing a full clinical evaluation, one night of polysomnography, a lumbar
      puncture to obtain cerebrospinal fluid, [11C]MRB PET-MR, and attention testing. This study
      has the potential to identify a new mechanism by which tau pathology contributes to sleep and
      attention dysfunction and may provide a new therapeutic target for AD prevention.
The purpose of this study is three-fold: to test whether lower NET availability in the LC is
      associated with: first, CSF tau levels typical of preclinical stages of AD (Aim 1); second,
      reduced REM and spindle density (Aim 2); and third, impaired performance on attention tasks
      (Aim 3). The goal is to test the overarching hypothesis that LC dysfunction occurs in
      preclinical AD stages, can be measured with MRB-PET, and translates into impairment of sleep
      architecture (LC tonic dysfunction) and attention (LC phasic dysfunction).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Methylreboxetine (MRB)-LC Mean Standardized Uptake Value Ratio (SUVR) Values
time frame: Visit 4 (1-4 weeks after LP)
measure: Total REM Duration (Min)
time frame: Visit 3 (1-4 weeks after Visit 2)
measure: Percentage of Time Spent in REM Sleep
time frame: Visit 3 (1-4 weeks after Visit 2)
measure: REM Sleep Continuity
time frame: Visit 3 (1-4 weeks after Visit 2)
description: Reported as percentage of REM runs that are less than 5, greater than or equal to 5 and greater than or equal to 10 minutes).
measure: N2 Spindle Density
time frame: Visit 3 (1-4 weeks after Visit 2)
measure: Mean Psychomotor Vigilance Test (PVT) Reaction Time
time frame: Visit 3 (1-4 weeks after Visit 2)
description: PVT measures the reaction speed to a randomly time-occuring visual stimuli, allowing the assessment of several aspects of attention including response times, attention lapses and false starts.
measure: Mean Oddball Test Response Time
time frame: Visit 3 (1-4 weeks after Visit 2)
description: The OddBall test measures task-related attention. Two different visual stimuli (frequent and infrequent) are presented in random succession as the subject presses a button only when the infrequent stimuli appears.
measure: Percentage of Correct Responses
time frame: Visit 3 (1-4 weeks after Visit 2)
measure: Levels of Hyperphosphorylated Tau (P-Tau, T-Tau)
time frame: Visit 4 (1-4 weeks after LP)
description: Levels will be derived from the CSF and reported in pg/mL
measure: Aβ42/Aβ40 Ratio
time frame: Visit 4 (1-4 weeks after LP)
description: The presence of amyloid plaques will be represented as the binary indicator of a CSF Aβ42/Aβ40 ratio
arm group label: Cognitively Normal (CN) Older Adults
arm group type: Experimental
intervention type: Procedure
intervention name: Nocturnal polysomnography (NPSG)
description: Nocturnal polysomnography (NPSG) to measure REM sleep and sleep spindles characteristics.
arm group label: Cognitively Normal (CN) Older Adults
intervention type: Procedure
intervention name: Lumbar Puncture (LP)
description: Lumbar puncture (LP) to measure CSF P-Tau, T-Tau and Aβ42/40 ratio.
arm group label: Cognitively Normal (CN) Older Adults
intervention type: Other
intervention name: PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]Omethylreboxetine ([11C]MRB)
description: PET-MR measurement with a norepinephrine transporter (NET)-selective radiotracer (S,S)-[11C]O-methylreboxetine ([11C]MRB) to measure NET availability.
arm group label: Cognitively Normal (CN) Older Adults
intervention type: Behavioral
intervention name: Psychomotor Vigilance Task (PVT)
description: Psychomotor vigilance task (PVT) and the OddBall to measure test taskattention performance.
arm group label: Cognitively Normal (CN) Older Adults
criteria: 
gender: All
minimum age: 60 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ricardo Osorio
role: Principal Investigator
affiliation: NYU Langone Health
last name: Dishari Azad
phone: 646-754-2229
email: Dishari.azad@nyulangone.org
last name: Ricardo Osorio
phone: 212-263-3255
email: ricardo.osorio@nyulangone.org
facility: 
status: Recruiting
facility: 
status: Not yet recruiting
country: United States
responsible party type: Sponsor
mesh term: Alzheimer Disease
mesh term: Norepinephrine
sharing ipd: Yes
ipd description: All of the individual participant data collected during the trial, after deidentification.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Immediately following publication. No end date.
ipd access criteria: The investigator who proposed to use the ricardo.osorio@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.