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/NCT05984446</url>
    </required_header>
    <id_info>
      <org_study_id>GR-2018-12368250</org_study_id>
      <nct_id>NCT05984446</nct_id>
    </id_info>
    <brief_title>Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease With Non-invasive Techniques</brief_title>
    <acronym>NEST4AD</acronym>
    <official_title>Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease With Non-invasive Techniques</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>IRCCS Centro San Giovanni di Dio Fatebenefratelli</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>IRCCS Centro San Giovanni di Dio Fatebenefratelli</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Default mode network (DMN) dysfunction is a well-established feature of Alzheimer's Disease&#xD;
        (AD) and is already present in preclinical stages and in subjects at risk for AD, thus&#xD;
        offering a potential target for early intervention. Non-invasive stimulation techniques are&#xD;
        candidate approaches to modulate network dysfunction, however interventions specifically&#xD;
        targeting subjects at risk for AD are lacking. This project will test a non-invasive&#xD;
        intervention to modulate the DMN in cognitively healthy older adults carrying the main&#xD;
        genetic risk factor for AD, the APOE e4 allele. The proposal will non-invasively stimulate&#xD;
        the DMN in at risk subjects and will assess the neuronal-cognitive effect of this approach&#xD;
        with multimodal neuroimaging and neurophysiological techniques.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Sixty-four participants will be enrolled (n=32 APOE e4 carriers, 32 non-carriers as reference&#xD;
        group) and will undergo rTMS stimulation, TMS with concurrent electroencephalography&#xD;
        (TMS-EEG), multimodal imaging (resting-state and task functional MRI, and diffusion tensor&#xD;
        imaging) and cognitive assessment at baseline, after the intervention (week 1) and after 2&#xD;
        months. Participants will be randomized to 2 groups: active DMN stimulation (real-rTMS) or&#xD;
        placebo (sham-rTMS). Each subject will undergo a rs-fMRI scan before the intervention to&#xD;
        derive individualized DMN stimulation targets. rTMS will be applied over the left inferior&#xD;
        parietal lobule node of the DMN.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">December 5, 2019</start_date>
    <completion_date type="Anticipated">December 4, 2024</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2024</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>
      <primary_purpose>Prevention</primary_purpose>
      <masking>Double (Participant, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in DMN connectivity on TMS-EEG following real-rTMS compared to sham-rTMS in APOE4 carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Memory is assessed on task fMRI using a face-name associative paradigm</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical e</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Memory is assessed on task fMRI using a face-name associative paradigm</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers</measure>
      <time_frame>Baseline, post rTMS (1 week)</time_frame>
      <description>Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers</measure>
      <time_frame>Baseline, post rTMS (2 months)</time_frame>
      <description>Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">64</enrollment>
    <condition>Alzheimer Disease</condition>
    <arm_group>
      <arm_group_label>real-rTMS</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>4 daily 25-minutes high-frequency rTMS sessions over one week</description>
    </arm_group>
    <arm_group>
      <arm_group_label>sham-rTMS</arm_group_label>
      <arm_group_type>Sham Comparator</arm_group_type>
      <description>4 daily 25-minutes sham-rTMS sessions over one week</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>real-rTMS</intervention_name>
      <description>Each subject will undergo 4 rTMS sessions using a 70-mm figure-eight coil (20Hz for 25 minutes). Target localization will be performed with a stereotaxic neuronavigation system.</description>
      <arm_group_label>real-rTMS</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>sham-rTMS</intervention_name>
      <description>The sham condition will match the real-rTMS protocol, but a sham coil will be used.</description>
      <arm_group_label>sham-rTMS</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age: 60 years and older&#xD;
  &#xD;
            -  MMSE score &gt; 24&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Pathological scores in at least two standardized cognitive tests&#xD;
  &#xD;
            -  Participation in other interventional studies&#xD;
  &#xD;
            -  Known carriers of an autosomal dominant genetic mutation associated to AD&#xD;
  &#xD;
            -  Neurological, psychiatric or medical conditions not compatible with the study&#xD;
  &#xD;
          Exclusion Criteria for MRI and rTMS:&#xD;
  &#xD;
            -  metal implants, pace-makers, prosthetic heart valves&#xD;
  &#xD;
            -  claustrophobia&#xD;
  &#xD;
            -  history of epilepsy&#xD;
  &#xD;
            -  pregnancy&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>60 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Michela Pievani</last_name>
      <role>Principal Investigator</role>
      <affiliation>IRCCS Centro San Giovanni di Dio Fatebenefratelli</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Michela Pievani</last_name>
      <phone>+39 030 3501311</phone>
      <email>mpievani@fatebenefratelli.eu</email>
    </overall_contact>
    <location>
      <facility>
        <name>IRCCS Centro San Giovanni di Dio Fatebenefratelli</name>
        <address>
          <city>Brescia</city>
          <zip>25125</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Michela Pievani, PhD</last_name>
        <phone>+39 030 3501311</phone>
        <email>mpievani@fatebenefratelli.eu</email>
      </contact>
      <investigator>
        <last_name>Michela Pievani, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <reference>
      <citation>Pievani M, Mega A, Quattrini G, Guidali G, Ferrari C, Cattaneo A, D'Aprile I, Mascaro L, Gasparotti R, Corbo D, Brignani D, Bortoletto M. Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design. J Alzheimers Dis. 2021;83(4):1877-1889. doi: 10.3233/JAD-210659.</citation>
      <PMID>34459405</PMID>
    </reference>
    <reference>
      <citation>Bagattini C, Brignani D, Bonni S, Quattrini G, Gasparotti R, Pievani M. Functional Imaging to Guide Network-Based TMS Treatments: Toward a Tailored Medicine Approach in Alzheimer's Disease. Front Neurosci. 2021 Jul 5;15:687493. doi: 10.3389/fnins.2021.687493. eCollection 2021.</citation>
      <PMID>34290585</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 2, 2023</study_first_submitted>
    <study_first_submitted_qc>August 2, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 9, 2023</study_first_posted>
    <last_update_submitted>August 2, 2023</last_update_submitted>
    <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 9, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>IRCCS Centro San Giovanni di Dio Fatebenefratelli</investigator_affiliation>
      <investigator_full_name>Michela Pievani</investigator_full_name>
      <investigator_title>Head, Lab Alzheimer's Neuroimaging &amp; Epidemiology</investigator_title>
    </responsible_party>
    <keyword>Alzheimer's disease</keyword>
    <keyword>Default mode network</keyword>
    <keyword>APOE</keyword>
    <keyword>rTMS</keyword>
    <keyword>connectivity</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Alzheimer Disease</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </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/NCT05984446
  org study id: GR-2018-12368250
  nct id: NCT05984446
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Default mode network (DMN) dysfunction is a well-established feature of Alzheimer's Disease
        (AD) and is already present in preclinical stages and in subjects at risk for AD, thus
        offering a potential target for early intervention. Non-invasive stimulation techniques are
        candidate approaches to modulate network dysfunction, however interventions specifically
        targeting subjects at risk for AD are lacking. This project will test a non-invasive
        intervention to modulate the DMN in cognitively healthy older adults carrying the main
        genetic risk factor for AD, the APOE e4 allele. The proposal will non-invasively stimulate
        the DMN in at risk subjects and will assess the neuronal-cognitive effect of this approach
        with multimodal neuroimaging and neurophysiological techniques.
  Sixty-four participants will be enrolled (n=32 APOE e4 carriers, 32 non-carriers as reference
        group) and will undergo rTMS stimulation, TMS with concurrent electroencephalography
        (TMS-EEG), multimodal imaging (resting-state and task functional MRI, and diffusion tensor
        imaging) and cognitive assessment at baseline, after the intervention (week 1) and after 2
        months. Participants will be randomized to 2 groups: active DMN stimulation (real-rTMS) or
        placebo (sham-rTMS). Each subject will undergo a rs-fMRI scan before the intervention to
        derive individualized DMN stimulation targets. rTMS will be applied over the left inferior
        parietal lobule node of the DMN.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Prevention
  masking: Double (Participant, Outcomes Assessor)
  measure: Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers
  time frame: Baseline, post rTMS (1 week)
  description: Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.
  measure: Change in DMN connectivity on TMS-EEG following real-rTMS compared to sham-rTMS in APOE4 carriers
  time frame: Baseline, post rTMS (1 week)
  description: Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs.
  measure: Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers
  time frame: Baseline, post rTMS (1 week)
  description: Memory is assessed on task fMRI using a face-name associative paradigm
  measure: Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-carriers
  time frame: Baseline, post rTMS (1 week)
  description: Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.
  measure: Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-carriers
  time frame: Baseline, post rTMS (1 week)
  description: Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical e
  measure: Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers
  time frame: Baseline, post rTMS (1 week)
  description: Memory is assessed on task fMRI using a face-name associative paradigm
  measure: Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers
  time frame: Baseline, post rTMS (1 week)
  description: Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.
  measure: Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers
  time frame: Baseline, post rTMS (1 week)
  description: Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.
  measure: Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers
  time frame: Baseline, post rTMS (2 months)
  description: Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.
  arm group label: real-rTMS
  arm group type: Experimental
  description: 4 daily 25-minutes high-frequency rTMS sessions over one week
  arm group label: sham-rTMS
  arm group type: Sham Comparator
  description: 4 daily 25-minutes sham-rTMS sessions over one week
  intervention type: Device
  intervention name: real-rTMS
  description: Each subject will undergo 4 rTMS sessions using a 70-mm figure-eight coil (20Hz for 25 minutes). Target localization will be performed with a stereotaxic neuronavigation system.
  arm group label: real-rTMS
  intervention type: Device
  intervention name: sham-rTMS
  description: The sham condition will match the real-rTMS protocol, but a sham coil will be used.
  arm group label: sham-rTMS
  criteria: 
  gender: All
  minimum age: 60 Years
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: Michela Pievani
  role: Principal Investigator
  affiliation: IRCCS Centro San Giovanni di Dio Fatebenefratelli
  last name: Michela Pievani
  phone: +39 030 3501311
  email: mpievani@fatebenefratelli.eu
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  country: Italy
  citation: Pievani M, Mega A, Quattrini G, Guidali G, Ferrari C, Cattaneo A, D'Aprile I, Mascaro L, Gasparotti R, Corbo D, Brignani D, Bortoletto M. Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design. J Alzheimers Dis. 2021;83(4):1877-1889. doi: 10.3233/JAD-210659.
  PMID: 34459405
  citation: Bagattini C, Brignani D, Bonni S, Quattrini G, Gasparotti R, Pievani M. Functional Imaging to Guide Network-Based TMS Treatments: Toward a Tailored Medicine Approach in Alzheimer's Disease. Front Neurosci. 2021 Jul 5;15:687493. doi: 10.3389/fnins.2021.687493. eCollection 2021.
  PMID: 34290585
  responsible party type: Principal Investigator
  investigator affiliation: IRCCS Centro San Giovanni di Dio Fatebenefratelli
  investigator full name: Michela Pievani
  investigator title: Head, Lab Alzheimer's Neuroimaging & Epidemiology
  mesh term: Alzheimer Disease
  sharing ipd: No