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/NCT05988385</url>
    </required_header>
    <id_info>
      <org_study_id>AG080609</org_study_id>
      <nct_id>NCT05988385</nct_id>
    </id_info>
    <brief_title>The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults Study</brief_title>
    <acronym>ESSENTIAL</acronym>
    <official_title>The Effects of Successful OSA Treatment on Memory and AD Biomarkers in Older Adults (ESSENTIAL) Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>California Pacific Medical Center Research Institute</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Icahn School of Medicine at Mount Sinai</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>New York University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of Arizona</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of Pittsburgh</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>National Institute on Aging (NIA)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
    </sponsors>
    <source>California Pacific Medical Center Research Institute</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>Yes</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts&#xD;
        (ESSENTIAL) study is a 5-year, multicenter randomized open-label trial that will screen 400&#xD;
        cognitively normal older adults recruited from well-established sleep clinics at 4 academic&#xD;
        medical centers, with newly diagnosed moderate-severe OSA. An expected 200 OSA patients will&#xD;
        be then randomized to one of two groups: i) a 3-month OSA treatment by any combination of&#xD;
        PAP, OAT, and positional therapy that results in an &quot;effective&quot; AHI4%&lt; 10/hour and&#xD;
        AHI3A&lt;20/hour (see below); ii) a waitlist control group to receive treatment at the&#xD;
        conclusion of the 3-month intervention period. Both groups will continue follow-up for 24&#xD;
        months on stable therapy to determine if sustained improvements in sleep are associated with&#xD;
        improvement in cognitive function and AD biomarkers.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The prevalence of Alzheimer disease (AD) is high and projected to increase. While there are&#xD;
        multiple risk factors for AD, epidemiological data suggests that ~15% of AD risk may be&#xD;
        attributed to sleep problems. Obstructive sleep apnea (OSA) is common among the elderly&#xD;
        (30-55%), and the investigators have shown that cognitively normal older women with OSA have&#xD;
        nearly double the risk of developing mild cognitive impairment (MCI) or dementia over 5&#xD;
        years. Further, the investigators have shown that in normal elderly, OSA predicts&#xD;
        longitudinal increases in AD biomarkers. Our preliminary data also show that after positive&#xD;
        airway pressure (PAP) withdrawal, OSA patients treated with PAP experienced significant&#xD;
        overnight increases in plasma neurofilament light (NfL), a marker of neural injury. The&#xD;
        present study is designed to overcome challenges identified in previous trials of treatment&#xD;
        of OSA to slow cognitive decline and progression to AD. First, the most effective treatment&#xD;
        for OSA, PAP therapy, has poor adherence (typically only 50% are adequately treated). Other&#xD;
        common therapies include oral appliance therapy (OAT) which tends to be better tolerated but&#xD;
        less effective. The investigators have piloted and propose for this study a rapid multimodal&#xD;
        therapy initiation (RMMT) which ensures subjects will have effective therapy for their OSA&#xD;
        that reduces OSA severity to AHI4%&lt;10/hour and AHI3A (AKA pRDI) &lt; 20/hour within 4 months.&#xD;
        Second, most prior OSA treatment trials have focused primarily on symptomatic older adults&#xD;
        (e.g. patients with MCI recruited from memory clinics), whereas early intervention in&#xD;
        pre-symptomatic individuals may have stronger impact in preventing progression to AD. The&#xD;
        investigators propose to enroll cognitively normal adults with newly diagnosed&#xD;
        moderate-severe OSA (AHI4% &gt;20/hour or AHI3A &gt; 40/hour). Finally, selection of cognitive&#xD;
        outcomes most responsive to OSA therapy has proved challenging. The Effects of Successful OSA&#xD;
        TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL) study is a 5-year,&#xD;
        multicenter randomized open-label trial that will screen 400 cognitively normal older adults&#xD;
        (MoCA≥24, Clinical Dementia Rating [CDR]=0), ages 55-75, recruited from well-established&#xD;
        sleep clinics at 4 academic medical centers, with newly diagnosed moderate-severe OSA (AHI4%&#xD;
        &gt;20/hour or AHI3A &gt; 40/hour). An expected 200 OSA patients will be then randomized to one of&#xD;
        two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy&#xD;
        that results in an &quot;effective&quot; AHI4%&lt; 10/hour and AHI3A&lt;20/hour (see below); ii) a waitlist&#xD;
        control group to receive treatment at the conclusion of the 3-month intervention period. Both&#xD;
        groups will continue follow-up for 24 months on stable therapy to determine if sustained&#xD;
        improvements in sleep are associated with improvement in cognitive function and AD&#xD;
        biomarkers. Both arms will include PSG and actigraphy, sleep-dependent memory and other&#xD;
        cognitive evaluations, and blood draws at baseline, 3 and 24 months, with cognitive&#xD;
        evaluation only at 12 months. Structural brain MRI will be performed at baseline. Because the&#xD;
        investigators anticipate that 150 of 200 subjects will be well treated at 24 months, and 50&#xD;
        will not be, the investigators will additionally recruit ~50 subjects (on average 13 subjects&#xD;
        per clinical site) with the same inclusion criteria who refuse treatment. These 50 subjects&#xD;
        will perform baseline (blood draw and cognitive evaluations), 12-month (cognitive evaluation&#xD;
        only), and 24-month (blood draw and cognitive evaluations) visits, allowing for a 24-month&#xD;
        comparison of ~150 subjects with adequate treatment over 24 months to 100 subjects with&#xD;
        inadequate treatment over 24 months. Our aims are: 1) To compare 3-month change in plasma AD&#xD;
        biomarkers (NfL, p-tau, Aβ) in those randomized to OSA treatment and wait-list control groups&#xD;
        (via both intention-to-treat and per-protocol analyses); 2) To test differences at 3 months&#xD;
        in sleep-dependent declarative memory and cognitive scores (PACC and sub-domains) between the&#xD;
        OSA treatment and wait-list control groups (via both intention-to-treat and per-protocol&#xD;
        analyses); 3) To compare 24-month changes in AD biomarkers (NfL, p-tau, Aβ) and cognition in&#xD;
        all successfully treated subjects and untreated controls.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">January 2024</start_date>
    <completion_date type="Anticipated">June 2028</completion_date>
    <primary_completion_date type="Anticipated">June 2028</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Approximately 250 total patients (~63 per site) will be enrolled. In the 3-month wait-list control randomized trial, 200 patients will be randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an &quot;effective&quot; AHI3a&lt;15 (rapid multi-modal treatment RMMT); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. The remaining 50, plus an additional ~50 (n~100 total) participants who declined treatment and were not interested in being randomized for the 3-month trial, or who have tried but failed treatment in the past, will serve as the &quot;control&quot; group for the 24-month follow-up period.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Change in overnight memory retention on the A-B verbal paired associates task</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in percent correct memory</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in overnight memory retention on the A-B verbal paired associates task</measure>
      <time_frame>12 months</time_frame>
      <description>Mean change in percent correct memory</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in overnight memory retention on the A-B verbal paired associates task</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in percent correct memory</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Aβ42/ Aβ40 ratio</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in the Aβ42/ Aβ40 ratio in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Aβ42/ Aβ40 ratio</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in the Aβ42/ Aβ40 ratio in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Plasma P-tau181</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in p-tau181 levels in the plasma in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Plasma P-tau181</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in p-tau181 levels in the plasma in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in P-tau217</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in p-tau217 levels in the plasma in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in P-tau217</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in p-tau217 levels in the plasma in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Neurofibrilary light (NfL)</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in NfL levels in the plasma in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Neurofibrilary light (NfL)</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in NfL levels in the plasma in picograms per millimeter (pg/ml)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Preclinical Cognitive Composite Score</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in Preclinical Cognitive Composite Score.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Preclinical Cognitive Composite Score</measure>
      <time_frame>12 months</time_frame>
      <description>Mean change in Preclinical Cognitive Composite Score.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Preclinical Cognitive Composite Score</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in Preclinical Cognitive Composite Score.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Change in Task-switching Accuracy</measure>
      <time_frame>3 months</time_frame>
      <description>Change in Task-switching Mean Percent Accuracy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Task-switching Accuracy</measure>
      <time_frame>12 months</time_frame>
      <description>Change in Task-switching Mean Percent Accuracy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Task-switching Accuracy</measure>
      <time_frame>24 months</time_frame>
      <description>Change in Task-switching Mean Percent Accuracy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Task-switching Reaction Time</measure>
      <time_frame>3 months</time_frame>
      <description>Change in Task-switching Mean Reaction Time in milliseconds</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Task-switching Reaction Time</measure>
      <time_frame>12 months</time_frame>
      <description>Change in Task-switching Mean Reaction Time in milliseconds</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Task-switching Reaction Time</measure>
      <time_frame>24 months</time_frame>
      <description>Change in Task-switching Mean Reaction Time in milliseconds</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Psychomotor Vigilance Task (PVT) lapses</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in number of lapses</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Psychomotor Vigilance Task (PVT) lapses</measure>
      <time_frame>12 months</time_frame>
      <description>Mean change in number of lapses</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Psychomotor Vigilance Task (PVT) lapses</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in number of lapses</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Psychomotor Vigilance Task (PVT) reaction time</measure>
      <time_frame>3 months</time_frame>
      <description>Mean change in median reaction time in milliseconds.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Psychomotor Vigilance Task (PVT) reaction time</measure>
      <time_frame>12 months</time_frame>
      <description>Mean change in median reaction time in milliseconds.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Psychomotor Vigilance Task (PVT) reaction time</measure>
      <time_frame>24 months</time_frame>
      <description>Mean change in median reaction time in milliseconds.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Cognitive Impairment Severity</measure>
      <time_frame>Baseline</time_frame>
      <description>Severity of cognitive impairment based on normed cutoffs with the National Alzheimer's Coordinating Centers Uniform Data Set-3 (UDS-3) assessment.</description>
    </other_outcome>
    <other_outcome>
      <measure>Cognitive Impairment Severity</measure>
      <time_frame>24 months</time_frame>
      <description>Severity of cognitive impairment based on normed cutoffs with the National Alzheimer's Coordinating Centers Uniform Data Set-3 (UDS-3) assessment.</description>
    </other_outcome>
    <other_outcome>
      <measure>Clinical Dementia Rating (CDR) Scale (0-3)</measure>
      <time_frame>Baseline</time_frame>
      <description>Clinical Dementia Rating on a scale of 0-3 based on clinical assessment, 0 being no impairment, and 3 being severe impairment.</description>
    </other_outcome>
    <other_outcome>
      <measure>Sleepiness Score</measure>
      <time_frame>Baseline</time_frame>
      <description>Epworth Sleepiness Scale (ESS) Questionnaire Score. Higher scores mean more severe sleepiness.</description>
    </other_outcome>
    <other_outcome>
      <measure>Sleepiness Score</measure>
      <time_frame>3 months</time_frame>
      <description>Epworth Sleepiness Scale (ESS) Questionnaire Score. Higher scores mean more severe sleepiness.</description>
    </other_outcome>
    <other_outcome>
      <measure>Sleepiness Score</measure>
      <time_frame>24 months</time_frame>
      <description>Epworth Sleepiness Scale (ESS) Questionnaire Score. Higher scores mean more severe sleepiness.</description>
    </other_outcome>
    <other_outcome>
      <measure>Insomnia Severity</measure>
      <time_frame>Baseline</time_frame>
      <description>Insomnia Severity Index (ISI) Questionnaire Score. Higher scores mean more severe insomnia symptoms.</description>
    </other_outcome>
    <other_outcome>
      <measure>Insomnia Severity</measure>
      <time_frame>3 months</time_frame>
      <description>Insomnia Severity Index (ISI) Questionnaire Score. Higher scores mean more severe insomnia symptoms.</description>
    </other_outcome>
    <other_outcome>
      <measure>Insomnia Severity</measure>
      <time_frame>24 months</time_frame>
      <description>Insomnia Severity Index (ISI) Questionnaire Score. Higher scores mean more severe insomnia symptoms.</description>
    </other_outcome>
    <other_outcome>
      <measure>Psychiatric Symptom Questionnaires: Geriatric Depression Scale (GDS)</measure>
      <time_frame>Baseline</time_frame>
      <description>Scores of 0-4 are considered normal, depending on age, education, and complaints; 5-8 indicate mild depression; 9-11 indicate moderate depression; and 12-15 indicate severe depression.</description>
    </other_outcome>
    <other_outcome>
      <measure>Psychiatric Symptom Questionnaires: Hamilton Anxiety Rating Scale (HAM-A)</measure>
      <time_frame>Baseline</time_frame>
      <description>Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where &lt;17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.</description>
    </other_outcome>
    <other_outcome>
      <measure>Psychiatric Symptom Questionnaires: Clinician-Administered PTSD Scale (CAPS)</measure>
      <time_frame>Baseline</time_frame>
      <description>CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: Criterion B (items 1-5); Criterion C (items 6-7); Criterion D (items 8-14); and, Criterion E (items 15-20). Severity scores range from 0-4, with 0 being absent to 4 being extreme/incapacitating.</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">250</enrollment>
    <condition>Obstructive Sleep Apnea</condition>
    <condition>Cognitive Decline</condition>
    <arm_group>
      <arm_group_label>3-month OSA treatment</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>A 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an &quot;effective&quot; AHI3a&lt;15 (rapid multi-modal treatment RMMT).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Waitlist control group</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>A waitlist control group to receive treatment at the conclusion of the 3-month intervention period.</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Positive airway pressure</intervention_name>
      <description>Positive airway pressure (PAP) therapy is a sleep apnea treatment that uses a stream of compressed air to support the airway during sleep. With PAP therapy, a mask is worn during sleep and a portable machine gently blows pressurized room air from into your upper airway through a tube connected to the mask. This positive airflow helps keep the airway open, preventing the collapse that occurs during apnea, thus allowing normal breathing.</description>
      <arm_group_label>3-month OSA treatment</arm_group_label>
      <arm_group_label>Waitlist control group</arm_group_label>
      <other_name>CPAP</other_name>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Oral appliance therapy</intervention_name>
      <description>Oral appliance therapy involves the use of a dental appliance or oral mandibular advancement device that prevents the tongue from blocking the throat and/or advances the lower jaw forward. These devices help keep the airway open during sleep.</description>
      <arm_group_label>3-month OSA treatment</arm_group_label>
      <arm_group_label>Waitlist control group</arm_group_label>
      <other_name>OAT</other_name>
      <other_name>ProSomnus</other_name>
      <other_name>Somnomed</other_name>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Positional therapy</intervention_name>
      <description>A NightShift Sleep Positioner (Advanced Brain Monitoring) is a neck vibration device, FDA approved to treat positional sleep apnea. The device detects patient supine position and delivers a small vibratory signal to the back of the neck to prompt position change.</description>
      <arm_group_label>3-month OSA treatment</arm_group_label>
      <arm_group_label>Waitlist control group</arm_group_label>
      <other_name>NightShift Sleep Positioner</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Cognitively normal (MoCA≥24, Clinical Dementia Rating [CDR]=0) with a minimum of 12&#xD;
               years of education&#xD;
  &#xD;
            -  Males and females, 55-75 years&#xD;
  &#xD;
            -  Moderate - severe OSA defined as AHI4 ≥20 events/hour or AHI3A&gt;40/hr using a Hypopnea&#xD;
               criterion of a 4% oxygen desaturation (AHI4) or 3% oxygen desaturation and/or EEG&#xD;
               arousal (AHI3A)&#xD;
  &#xD;
            -  No OSA treatment&#xD;
  &#xD;
            -  Able and willing to be treated for OSA&#xD;
  &#xD;
            -  Fluency in English or Spanish&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Any other sleep or breathing disorder requiring supplemental oxygen. This includes&#xD;
               circadian rhythm abnormalities, including irregular sleep-wake cycles defined as&#xD;
               self-reported '≥3 sleep episodes per 24-hr period' or 'day to day irregularity of&#xD;
               sleep/wake times greater than 2 hours'&#xD;
  &#xD;
            -  Anticipated scheduled bariatric surgery&#xD;
  &#xD;
            -  Chronic use of any sedative, stimulant, neuroleptic drugs, or other medications&#xD;
               limiting validity of cognitive tests&#xD;
  &#xD;
            -  The presence of critical comorbid conditions, including clinically relevant endocrine&#xD;
               or hematological conditions, substance abuse, preexisting cognitive, psychiatric, or&#xD;
               neurological conditions, and pregnancy. History of stroke or MRI evidence of vascular&#xD;
               damage, history of transient ischemic attacks or extensive white matter lesions&#xD;
               (Fazekas scale &gt;2) will also be excluded.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>55 Years</minimum_age>
      <maximum_age>75 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Katie L Stone, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>California Pacific Medical Center Research Institute</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Ricardo Osorio, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>New York University</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Andrew Varga, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Dana R Kriesel, MPH</last_name>
      <phone>415-476-6128</phone>
      <email>dana.kriesel@ucsf.edu</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Katie L Stone, PhD</last_name>
      <phone>415-476-6128</phone>
      <email>katie.stone@ucsf.edu</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>University of Arizona</name>
        <address>
          <city>Tucson</city>
          <state>Arizona</state>
          <zip>85719</zip>
          <country>United States</country>
        </address>
      </facility>
      <investigator>
        <last_name>Sairam Parsasarathy, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>New York University</name>
        <address>
          <city>New York</city>
          <state>New York</state>
          <zip>10016</zip>
          <country>United States</country>
        </address>
      </facility>
      <investigator>
        <last_name>Acibiades Rodriguez, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Ricardo Osorio, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Mount Sinai</name>
        <address>
          <city>New York</city>
          <state>New York</state>
          <zip>10023</zip>
          <country>United States</country>
        </address>
      </facility>
      <investigator>
        <last_name>Andrew Varga, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Jay Guevarra, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>University of Pittsburgh</name>
        <address>
          <city>Pittsburgh</city>
          <state>Pennsylvania</state>
          <zip>15213</zip>
          <country>United States</country>
        </address>
      </facility>
      <investigator>
        <last_name>Sanjay Patel, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>June 2023</verification_date>
    <study_first_submitted>May 22, 2023</study_first_submitted>
    <study_first_submitted_qc>August 4, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 4, 2023</last_update_submitted>
    <last_update_submitted_qc>August 4, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Obstructive Sleep Apnea</keyword>
    <keyword>OSA</keyword>
    <keyword>Cognitive decline</keyword>
    <keyword>Alzheimer Disease</keyword>
    <keyword>AD</keyword>
    <keyword>AD biomarkers</keyword>
    <keyword>Positive Airway Pressure</keyword>
    <keyword>PAP</keyword>
    <keyword>CPAP</keyword>
    <keyword>Oral appliance therapy</keyword>
    <keyword>OAT</keyword>
    <keyword>Positional therapy</keyword>
    <keyword>Sleep-dependent memory</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sleep Apnea Syndromes</mesh_term>
      <mesh_term>Sleep Apnea, Obstructive</mesh_term>
      <mesh_term>Cognitive Dysfunction</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>The final research data will be available in acceptable formats commonly accepted for documenting and supporting research findings. All data will be released and/or shared as soon as feasible without compromising privacy concerns, federal and state confidentiality concerns, proprietary interests, national security interests, or law enforcement activities. The final research data will not contain any patient identifiers. Even though the final dataset will be stripped of identifiers prior to release for sharing, we believe that there remains the possibility of deductive disclosure of subjects with unusual characteristics. Thus, we will make the data and associated documentation available to users only under a data-sharing agreement.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_time_frame>Research data that documents, supports, and validates research findings will be available after the main findings from the final research data set are accepted for publication. We anticipate data will be available starting in January 2029 and will be available on an NIH-sponsored platform for as long as the agency supports it.</ipd_time_frame>
      <ipd_access_criteria>Data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.</ipd_access_criteria>
    </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/NCT05988385
  org study id: AG080609
  nct id: NCT05988385
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: Yes
  The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts
        (ESSENTIAL) study is a 5-year, multicenter randomized open-label trial that will screen 400
        cognitively normal older adults recruited from well-established sleep clinics at 4 academic
        medical centers, with newly diagnosed moderate-severe OSA. An expected 200 OSA patients will
        be then randomized to one of two groups: i) a 3-month OSA treatment by any combination of
        PAP, OAT, and positional therapy that results in an "effective" AHI4%< 10/hour and
        AHI3A<20/hour (see below); ii) a waitlist control group to receive treatment at the
        conclusion of the 3-month intervention period. Both groups will continue follow-up for 24
        months on stable therapy to determine if sustained improvements in sleep are associated with
        improvement in cognitive function and AD biomarkers.
  The prevalence of Alzheimer disease (AD) is high and projected to increase. While there are
        multiple risk factors for AD, epidemiological data suggests that ~15% of AD risk may be
        attributed to sleep problems. Obstructive sleep apnea (OSA) is common among the elderly
        (30-55%), and the investigators have shown that cognitively normal older women with OSA have
        nearly double the risk of developing mild cognitive impairment (MCI) or dementia over 5
        years. Further, the investigators have shown that in normal elderly, OSA predicts
        longitudinal increases in AD biomarkers. Our preliminary data also show that after positive
        airway pressure (PAP) withdrawal, OSA patients treated with PAP experienced significant
        overnight increases in plasma neurofilament light (NfL), a marker of neural injury. The
        present study is designed to overcome challenges identified in previous trials of treatment
        of OSA to slow cognitive decline and progression to AD. First, the most effective treatment
        for OSA, PAP therapy, has poor adherence (typically only 50% are adequately treated). Other
        common therapies include oral appliance therapy (OAT) which tends to be better tolerated but
        less effective. The investigators have piloted and propose for this study a rapid multimodal
        therapy initiation (RMMT) which ensures subjects will have effective therapy for their OSA
        that reduces OSA severity to AHI4%<10/hour and AHI3A (AKA pRDI) < 20/hour within 4 months.
        Second, most prior OSA treatment trials have focused primarily on symptomatic older adults
        (e.g. patients with MCI recruited from memory clinics), whereas early intervention in
        pre-symptomatic individuals may have stronger impact in preventing progression to AD. The
        investigators propose to enroll cognitively normal adults with newly diagnosed
        moderate-severe OSA (AHI4% >20/hour or AHI3A > 40/hour). Finally, selection of cognitive
        outcomes most responsive to OSA therapy has proved challenging. The Effects of Successful OSA
        TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL) study is a 5-year,
        multicenter randomized open-label trial that will screen 400 cognitively normal older adults
        (MoCA≥24, Clinical Dementia Rating [CDR]=0), ages 55-75, recruited from well-established
        sleep clinics at 4 academic medical centers, with newly diagnosed moderate-severe OSA (AHI4%
        >20/hour or AHI3A > 40/hour). An expected 200 OSA patients will be then randomized to one of
        two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy
        that results in an "effective" AHI4%< 10/hour and AHI3A<20/hour (see below); ii) a waitlist
        control group to receive treatment at the conclusion of the 3-month intervention period. Both
        groups will continue follow-up for 24 months on stable therapy to determine if sustained
        improvements in sleep are associated with improvement in cognitive function and AD
        biomarkers. Both arms will include PSG and actigraphy, sleep-dependent memory and other
        cognitive evaluations, and blood draws at baseline, 3 and 24 months, with cognitive
        evaluation only at 12 months. Structural brain MRI will be performed at baseline. Because the
        investigators anticipate that 150 of 200 subjects will be well treated at 24 months, and 50
        will not be, the investigators will additionally recruit ~50 subjects (on average 13 subjects
        per clinical site) with the same inclusion criteria who refuse treatment. These 50 subjects
        will perform baseline (blood draw and cognitive evaluations), 12-month (cognitive evaluation
        only), and 24-month (blood draw and cognitive evaluations) visits, allowing for a 24-month
        comparison of ~150 subjects with adequate treatment over 24 months to 100 subjects with
        inadequate treatment over 24 months. Our aims are: 1) To compare 3-month change in plasma AD
        biomarkers (NfL, p-tau, Aβ) in those randomized to OSA treatment and wait-list control groups
        (via both intention-to-treat and per-protocol analyses); 2) To test differences at 3 months
        in sleep-dependent declarative memory and cognitive scores (PACC and sub-domains) between the
        OSA treatment and wait-list control groups (via both intention-to-treat and per-protocol
        analyses); 3) To compare 24-month changes in AD biomarkers (NfL, p-tau, Aβ) and cognition in
        all successfully treated subjects and untreated controls.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Approximately 250 total patients (~63 per site) will be enrolled. In the 3-month wait-list control randomized trial, 200 patients will be randomized to one of two groups: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI3a<15 (rapid multi-modal treatment RMMT); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. The remaining 50, plus an additional ~50 (n~100 total) participants who declined treatment and were not interested in being randomized for the 3-month trial, or who have tried but failed treatment in the past, will serve as the "control" group for the 24-month follow-up period.
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Change in overnight memory retention on the A-B verbal paired associates task
  time frame: 3 months
  description: Mean change in percent correct memory
  measure: Change in overnight memory retention on the A-B verbal paired associates task
  time frame: 12 months
  description: Mean change in percent correct memory
  measure: Change in overnight memory retention on the A-B verbal paired associates task
  time frame: 24 months
  description: Mean change in percent correct memory
  measure: Change in Aβ42/ Aβ40 ratio
  time frame: 3 months
  description: Mean change in the Aβ42/ Aβ40 ratio in picograms per millimeter (pg/ml)
  measure: Change in Aβ42/ Aβ40 ratio
  time frame: 24 months
  description: Mean change in the Aβ42/ Aβ40 ratio in picograms per millimeter (pg/ml)
  measure: Change in Plasma P-tau181
  time frame: 3 months
  description: Mean change in p-tau181 levels in the plasma in picograms per millimeter (pg/ml)
  measure: Change in Plasma P-tau181
  time frame: 24 months
  description: Mean change in p-tau181 levels in the plasma in picograms per millimeter (pg/ml)
  measure: Change in P-tau217
  time frame: 3 months
  description: Mean change in p-tau217 levels in the plasma in picograms per millimeter (pg/ml)
  measure: Change in P-tau217
  time frame: 24 months
  description: Mean change in p-tau217 levels in the plasma in picograms per millimeter (pg/ml)
  measure: Change in Neurofibrilary light (NfL)
  time frame: 3 months
  description: Mean change in NfL levels in the plasma in picograms per millimeter (pg/ml)
  measure: Change in Neurofibrilary light (NfL)
  time frame: 24 months
  description: Mean change in NfL levels in the plasma in picograms per millimeter (pg/ml)
  measure: Preclinical Cognitive Composite Score
  time frame: 3 months
  description: Mean change in Preclinical Cognitive Composite Score.
  measure: Preclinical Cognitive Composite Score
  time frame: 12 months
  description: Mean change in Preclinical Cognitive Composite Score.
  measure: Preclinical Cognitive Composite Score
  time frame: 24 months
  description: Mean change in Preclinical Cognitive Composite Score.
  measure: Change in Task-switching Accuracy
  time frame: 3 months
  description: Change in Task-switching Mean Percent Accuracy
  measure: Change in Task-switching Accuracy
  time frame: 12 months
  description: Change in Task-switching Mean Percent Accuracy
  measure: Change in Task-switching Accuracy
  time frame: 24 months
  description: Change in Task-switching Mean Percent Accuracy
  measure: Change in Task-switching Reaction Time
  time frame: 3 months
  description: Change in Task-switching Mean Reaction Time in milliseconds
  measure: Change in Task-switching Reaction Time
  time frame: 12 months
  description: Change in Task-switching Mean Reaction Time in milliseconds
  measure: Change in Task-switching Reaction Time
  time frame: 24 months
  description: Change in Task-switching Mean Reaction Time in milliseconds
  measure: Change in Psychomotor Vigilance Task (PVT) lapses
  time frame: 3 months
  description: Mean change in number of lapses
  measure: Change in Psychomotor Vigilance Task (PVT) lapses
  time frame: 12 months
  description: Mean change in number of lapses
  measure: Change in Psychomotor Vigilance Task (PVT) lapses
  time frame: 24 months
  description: Mean change in number of lapses
  measure: Change in Psychomotor Vigilance Task (PVT) reaction time
  time frame: 3 months
  description: Mean change in median reaction time in milliseconds.
  measure: Change in Psychomotor Vigilance Task (PVT) reaction time
  time frame: 12 months
  description: Mean change in median reaction time in milliseconds.
  measure: Change in Psychomotor Vigilance Task (PVT) reaction time
  time frame: 24 months
  description: Mean change in median reaction time in milliseconds.
  measure: Cognitive Impairment Severity
  time frame: Baseline
  description: Severity of cognitive impairment based on normed cutoffs with the National Alzheimer's Coordinating Centers Uniform Data Set-3 (UDS-3) assessment.
  measure: Cognitive Impairment Severity
  time frame: 24 months
  description: Severity of cognitive impairment based on normed cutoffs with the National Alzheimer's Coordinating Centers Uniform Data Set-3 (UDS-3) assessment.
  measure: Clinical Dementia Rating (CDR) Scale (0-3)
  time frame: Baseline
  description: Clinical Dementia Rating on a scale of 0-3 based on clinical assessment, 0 being no impairment, and 3 being severe impairment.
  measure: Sleepiness Score
  time frame: Baseline
  description: Epworth Sleepiness Scale (ESS) Questionnaire Score. Higher scores mean more severe sleepiness.
  measure: Sleepiness Score
  time frame: 3 months
  description: Epworth Sleepiness Scale (ESS) Questionnaire Score. Higher scores mean more severe sleepiness.
  measure: Sleepiness Score
  time frame: 24 months
  description: Epworth Sleepiness Scale (ESS) Questionnaire Score. Higher scores mean more severe sleepiness.
  measure: Insomnia Severity
  time frame: Baseline
  description: Insomnia Severity Index (ISI) Questionnaire Score. Higher scores mean more severe insomnia symptoms.
  measure: Insomnia Severity
  time frame: 3 months
  description: Insomnia Severity Index (ISI) Questionnaire Score. Higher scores mean more severe insomnia symptoms.
  measure: Insomnia Severity
  time frame: 24 months
  description: Insomnia Severity Index (ISI) Questionnaire Score. Higher scores mean more severe insomnia symptoms.
  measure: Psychiatric Symptom Questionnaires: Geriatric Depression Scale (GDS)
  time frame: Baseline
  description: Scores of 0-4 are considered normal, depending on age, education, and complaints; 5-8 indicate mild depression; 9-11 indicate moderate depression; and 12-15 indicate severe depression.
  measure: Psychiatric Symptom Questionnaires: Hamilton Anxiety Rating Scale (HAM-A)
  time frame: Baseline
  description: Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
  measure: Psychiatric Symptom Questionnaires: Clinician-Administered PTSD Scale (CAPS)
  time frame: Baseline
  description: CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for symptoms corresponding to a given DSM-5 cluster: Criterion B (items 1-5); Criterion C (items 6-7); Criterion D (items 8-14); and, Criterion E (items 15-20). Severity scores range from 0-4, with 0 being absent to 4 being extreme/incapacitating.
  arm group label: 3-month OSA treatment
  arm group type: Active Comparator
  description: A 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an "effective" AHI3a<15 (rapid multi-modal treatment RMMT).
  arm group label: Waitlist control group
  arm group type: Other
  description: A waitlist control group to receive treatment at the conclusion of the 3-month intervention period.
  intervention type: Device
  intervention name: Positive airway pressure
  description: Positive airway pressure (PAP) therapy is a sleep apnea treatment that uses a stream of compressed air to support the airway during sleep. With PAP therapy, a mask is worn during sleep and a portable machine gently blows pressurized room air from into your upper airway through a tube connected to the mask. This positive airflow helps keep the airway open, preventing the collapse that occurs during apnea, thus allowing normal breathing.
  arm group label: 3-month OSA treatment
  arm group label: Waitlist control group
  other name: CPAP
  intervention type: Device
  intervention name: Oral appliance therapy
  description: Oral appliance therapy involves the use of a dental appliance or oral mandibular advancement device that prevents the tongue from blocking the throat and/or advances the lower jaw forward. These devices help keep the airway open during sleep.
  arm group label: 3-month OSA treatment
  arm group label: Waitlist control group
  other name: OAT
  other name: ProSomnus
  other name: Somnomed
  intervention type: Device
  intervention name: Positional therapy
  description: A NightShift Sleep Positioner (Advanced Brain Monitoring) is a neck vibration device, FDA approved to treat positional sleep apnea. The device detects patient supine position and delivers a small vibratory signal to the back of the neck to prompt position change.
  arm group label: 3-month OSA treatment
  arm group label: Waitlist control group
  other name: NightShift Sleep Positioner
  criteria: 
  gender: All
  minimum age: 55 Years
  maximum age: 75 Years
  healthy volunteers: No
  last name: Katie L Stone, PhD
  role: Principal Investigator
  affiliation: California Pacific Medical Center Research Institute
  last name: Ricardo Osorio, MD
  role: Principal Investigator
  affiliation: New York University
  last name: Andrew Varga, MD
  role: Principal Investigator
  affiliation: Icahn School of Medicine at Mount Sinai
  last name: Dana R Kriesel, MPH
  phone: 415-476-6128
  email: dana.kriesel@ucsf.edu
  last name: Katie L Stone, PhD
  phone: 415-476-6128
  email: katie.stone@ucsf.edu
  facility: 
  investigator: 
  facility: 
  investigator: 
  investigator: 
  facility: 
  investigator: 
  investigator: 
  facility: 
  investigator: 
  country: United States
  responsible party type: Sponsor
  mesh term: Sleep Apnea Syndromes
  mesh term: Sleep Apnea, Obstructive
  mesh term: Cognitive Dysfunction
  sharing ipd: Yes
  ipd description: The final research data will be available in acceptable formats commonly accepted for documenting and supporting research findings. All data will be released and/or shared as soon as feasible without compromising privacy concerns, federal and state confidentiality concerns, proprietary interests, national security interests, or law enforcement activities. The final research data will not contain any patient identifiers. Even though the final dataset will be stripped of identifiers prior to release for sharing, we believe that there remains the possibility of deductive disclosure of subjects with unusual characteristics. Thus, we will make the data and associated documentation available to users only under a data-sharing agreement.
  ipd info type: Study Protocol
  ipd info type: Informed Consent Form (ICF)
  ipd time frame: Research data that documents, supports, and validates research findings will be available after the main findings from the final research data set are accepted for publication. We anticipate data will be available starting in January 2029 and will be available on an NIH-sponsored platform for as long as the agency supports it.
  ipd access criteria: Data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.