<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/NCT03778151</url>
  </required_header>
  <id_info>
    <org_study_id>RC-2018</org_study_id>
    <nct_id>NCT03778151</nct_id>
  </id_info>
  <brief_title>Repetitive TMS of the Default Mode Network in AD</brief_title>
  <acronym>TMS-AD</acronym>
  <official_title>Repetitive TMS of the Precuneus: a Randomized Double-blinded Placebo-controlled Trial in Alzheimer's Disease Patients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>I.R.C.C.S. Fondazione Santa Lucia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>I.R.C.C.S. Fondazione Santa Lucia</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alzheimer's disease is a global health challenge. Efforts aim at developing an effective&#xD;
      treatment able to meet the needs of patients and their families. Thus, the primary aim of&#xD;
      this project is to investigate the efficacy of a non-invasive brain stimulation, namely&#xD;
      repetitive transcranial magnetic stimulation (rTMS), on cognition in patients with mild&#xD;
      Alzheimer's disease. rTMS is considered a safe, well tolerated and relatively cheap&#xD;
      treatment. The appealing idea of the intervention is to improve memory by directly modulating&#xD;
      the activity of precuneus, key area linked to memory impairment. Patients will be treated&#xD;
      with rTMS in two phases: an intensive phase and a maintenance phase for a total of six&#xD;
      months. This project aims to provide a valid treatment to slow the worsening of symptoms and&#xD;
      improve quality of life for those with Alzheimer's and their caregivers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by severe&#xD;
      disruption of large-scale brain networks connectivity. AD pathophysiology has been mainly&#xD;
      associated with a breakdown of the Default Mode Network (DMN) and with a structural&#xD;
      disconnection of parietal nodes. It has been shown that the precuneus (PC), a central hub of&#xD;
      the DMN, is involved in successful episodic memory retrieval, working as a key area of the&#xD;
      network activated by recognition memory. Recent anatomical works have shown that medial&#xD;
      parietal regions are interconnected with the medial temporal region, which is implicated in&#xD;
      memory retrieval. In particular, the PC was identified as a region demonstrating strong&#xD;
      functional interconnectivity with the hippocampal formation. This is of particular relevance&#xD;
      because PC is altered in AD. At early clinical stages of AD, PC is selectively vulnerable to&#xD;
      early amyloid deposition, and plays a critical role in the conversion towards dementia.&#xD;
&#xD;
      Hypothesis: a novel therapeutic intervention for AD is repetitive Transcranial Magnetic&#xD;
      Stimulation (rTMS). rTMS is a non- invasive approach that can be used to induce long lasting&#xD;
      modulation of specific brain functions, inducing neuroplastic changes not only in the&#xD;
      cortical site of stimulation, but also in remote interconnected areas. In a recent double&#xD;
      blind randomized cross-over clinical pilot study, we found that a two-week course of daily&#xD;
      high-frequency rTMS (20 Hz) treatment targeting the DMN (Stimulation site: PC) was able to&#xD;
      induce an improvement in episodic memory compared to placebo. Indeed, TMS-EEG measurements&#xD;
      showed that rTMS treatment, applied over the DMN, was capable to modulate the cortical&#xD;
      activity in both the targeted areas (PC) as well as in functional connected regions of the&#xD;
      DMN (Koch et al., 2018).&#xD;
&#xD;
      Specific aims: to investigate clinical efficacy and safety of DMN rTMS applied during 6&#xD;
      months in mild AD patients. To provide novel evidence that non-invasive treatment of network&#xD;
      dysfunction, through stimulation of the PC, will represent an effective strategy to enhance&#xD;
      cognitive functions and lead to substantial slowing of cognitive and functional decline in&#xD;
      patients with mild AD. The findings yielded by the present project will have a potential&#xD;
      strong impact on clinical practice of AD patients. Since rTMS is well tolerated and&#xD;
      relatively low-priced, a positive result could lead to a fast application of the present&#xD;
      proposal to the clinical experience. If successful, the proposed project will provide support&#xD;
      for a novel treatment for cognitive dysfunction in AD patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 1, 2018</start_date>
  <completion_date type="Actual">October 1, 2020</completion_date>
  <primary_completion_date type="Actual">August 30, 2020</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Dementia Rating scale (CDR) sum of boxes</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>global cognition</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>global cognition</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>functional activities</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychiatric Inventory (NPI)</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>behavioural symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frontal Assessment Battery (FAB)</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>frontal lobe functions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immediate and delayed total recall score from the Rey Auditory Verbal Learning test (RAVLT)</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>memory</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortical activity (TMS-EEG)</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>neurophysiological marker</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>TRANSCRANIAL MAGNETIC STIMULATION</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>repetitive TRANSCRANIAL MAGNETIC STIMULATION (rTMS) will be applied over the precuneus to modulate DMN activity. The rTMS treatment will consist of two phases: an intensive phase and a maintenance phase. The intensive phase will involve 2 weeks of treatment, 5 days per week (10 sessions, 1.600 pulses per day for a total of 16.000 pulses). The maintenance phase will consist of 1 session of treatment every week for 5 months (21 sessions, 100.800 pulses in total).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SHAM TRANSCRANIAL MAGNETIC STIMULATION</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>SHAM TMS will be applied over the precuneus. The SHAM protocol will consist of two phases: an intensive phase and a maintenance phase. The intensive phase will involve 2 weeks of treatment, 5 days per week (10 sessions, 1.600 pulses per day for a total of 16.000 pulses). The maintenance phase will consist of 1 session of treatment every week for 5 months (21 sessions, 100.800 pulses in total).</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION</intervention_name>
    <description>daily treatment session of REPETITIVE TRANSCRANIAL MAGNETIC STIMULATIO will be applied over precuneus for 20 minutes of consecutive blocks of 20Hz pulses for two seconds followed by 28 seconds of no stimulation.</description>
    <arm_group_label>SHAM TRANSCRANIAL MAGNETIC STIMULATION</arm_group_label>
    <arm_group_label>TRANSCRANIAL MAGNETIC STIMULATION</arm_group_label>
    <other_name>RTMS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The patient and the responsible caregiver have signed the Informed Consent Form.&#xD;
&#xD;
          2. The patient has probable AD, diagnosed according to NINCDS-ADRDA criteria.&#xD;
&#xD;
          3. The patient is a man or woman, aged ≤ 85 years.&#xD;
&#xD;
          4. The patient has a CDR total score of 0.5 or 1 (mild) and MMSE score of 18-26&#xD;
             (inclusive) at Screening.&#xD;
&#xD;
          5. Has at least one identified adult caregiver&#xD;
&#xD;
          6. The patient has been treated with acetylcholinesterase inhibitor (AChEI), i.e.,&#xD;
             donepezil, galantamine, or rivastigmine, at the time of Screening&#xD;
&#xD;
               -  For at least 3 months&#xD;
&#xD;
               -  The current dosage regimen must have remained stable for ≥ 8 weeks&#xD;
&#xD;
               -  It must be planned that the dosage regimen will remain stable throughout&#xD;
                  participation in the study&#xD;
&#xD;
          7. The patient is able to comply with the study procedures in the view of the&#xD;
             investigator.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Significant neurodegenerative disorder of the central nervous system other than&#xD;
             Alzheimer's disease&#xD;
&#xD;
          2. Significant intracranial focal or vascular pathology seen on brain MRI scan&#xD;
&#xD;
          3. History of seizure (with the exception of febrile seizures in childhood)&#xD;
&#xD;
          4. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision&#xD;
             (DSM IV-TR) criteria met for any of the following within specified period:&#xD;
&#xD;
               -  Major depressive disorder (current)&#xD;
&#xD;
               -  Schizophrenia (lifetime)&#xD;
&#xD;
               -  Other psychotic disorders, bipolar disorder, or substance (including alcohol)&#xD;
                  related disorders (within the past 5 years)&#xD;
&#xD;
          5. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other&#xD;
             non-removable items that are contraindications to MR imaging.&#xD;
&#xD;
          6. Treatment currently or within 3 months before Baseline with any of the following&#xD;
             medications:&#xD;
&#xD;
               -  Typical and atypical antipsychotics (i.e. Clozapine, Olanzapine)&#xD;
&#xD;
               -  Antiepileptics drugs (i.e. Carbamazepine, Primidone, Pregabalin, Gabapentin)&#xD;
&#xD;
               -  Memantine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Caterina Motta</last_name>
    <role>Study Director</role>
    <affiliation>Santa Lucia Foundation</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Giacomo Koch</name>
      <address>
        <city>Rome</city>
        <zip>00179</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Santa Lucia Foundation</name>
      <address>
        <city>Rome</city>
        <zip>00179</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.</citation>
    <PMID>29277405</PMID>
  </reference>
  <reference>
    <citation>Di Lorenzo F, Ponzo V, Bonni S, Motta C, Negrao Serra PC, Bozzali M, Caltagirone C, Martorana A, Koch G. Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset. Ann Neurol. 2016 Aug;80(2):202-10. doi: 10.1002/ana.24695. Epub 2016 Jul 8.</citation>
    <PMID>27255833</PMID>
  </reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 14, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>February 5, 2021</last_update_submitted>
  <last_update_submitted_qc>February 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>I.R.C.C.S. Fondazione Santa Lucia</investigator_affiliation>
    <investigator_full_name>Giacomo Koch</investigator_full_name>
    <investigator_title>Head of Laboratory</investigator_title>
  </responsible_party>
  <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>Undecided</sharing_ipd>
    <ipd_description>It is not yet known if there will be a plan to make IPD available.</ipd_description>
  </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/NCT03778151
org study id: RC-2018
nct id: NCT03778151
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Alzheimer's disease is a global health challenge. Efforts aim at developing an effective
      treatment able to meet the needs of patients and their families. Thus, the primary aim of
      this project is to investigate the efficacy of a non-invasive brain stimulation, namely
      repetitive transcranial magnetic stimulation (rTMS), on cognition in patients with mild
      Alzheimer's disease. rTMS is considered a safe, well tolerated and relatively cheap
      treatment. The appealing idea of the intervention is to improve memory by directly modulating
      the activity of precuneus, key area linked to memory impairment. Patients will be treated
      with rTMS in two phases: an intensive phase and a maintenance phase for a total of six
      months. This project aims to provide a valid treatment to slow the worsening of symptoms and
      improve quality of life for those with Alzheimer's and their caregivers.
Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by severe
      disruption of large-scale brain networks connectivity. AD pathophysiology has been mainly
      associated with a breakdown of the Default Mode Network (DMN) and with a structural
      disconnection of parietal nodes. It has been shown that the precuneus (PC), a central hub of
      the DMN, is involved in successful episodic memory retrieval, working as a key area of the
      network activated by recognition memory. Recent anatomical works have shown that medial
      parietal regions are interconnected with the medial temporal region, which is implicated in
      memory retrieval. In particular, the PC was identified as a region demonstrating strong
      functional interconnectivity with the hippocampal formation. This is of particular relevance
      because PC is altered in AD. At early clinical stages of AD, PC is selectively vulnerable to
      early amyloid deposition, and plays a critical role in the conversion towards dementia.

      Hypothesis: a novel therapeutic intervention for AD is repetitive Transcranial Magnetic
      Stimulation (rTMS). rTMS is a non- invasive approach that can be used to induce long lasting
      modulation of specific brain functions, inducing neuroplastic changes not only in the
      cortical site of stimulation, but also in remote interconnected areas. In a recent double
      blind randomized cross-over clinical pilot study, we found that a two-week course of daily
      high-frequency rTMS (20 Hz) treatment targeting the DMN (Stimulation site: PC) was able to
      induce an improvement in episodic memory compared to placebo. Indeed, TMS-EEG measurements
      showed that rTMS treatment, applied over the DMN, was capable to modulate the cortical
      activity in both the targeted areas (PC) as well as in functional connected regions of the
      DMN (Koch et al., 2018).

      Specific aims: to investigate clinical efficacy and safety of DMN rTMS applied during 6
      months in mild AD patients. To provide novel evidence that non-invasive treatment of network
      dysfunction, through stimulation of the PC, will represent an effective strategy to enhance
      cognitive functions and lead to substantial slowing of cognitive and functional decline in
      patients with mild AD. The findings yielded by the present project will have a potential
      strong impact on clinical practice of AD patients. Since rTMS is well tolerated and
      relatively low-priced, a positive result could lead to a fast application of the present
      proposal to the clinical experience. If successful, the proposed project will provide support
      for a novel treatment for cognitive dysfunction in AD patients.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Clinical Dementia Rating scale (CDR) sum of boxes
time frame: change from baseline to Week 24
description: global cognition
measure: Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)
time frame: change from baseline to Week 24
description: global cognition
measure: Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
time frame: change from baseline to Week 24
description: functional activities
measure: Neuropsychiatric Inventory (NPI)
time frame: change from baseline to Week 24
description: behavioural symptoms
measure: Frontal Assessment Battery (FAB)
time frame: change from baseline to Week 24
description: frontal lobe functions
measure: Immediate and delayed total recall score from the Rey Auditory Verbal Learning test (RAVLT)
time frame: change from baseline to Week 24
description: memory
measure: Cortical activity (TMS-EEG)
time frame: change from baseline to Week 24
description: neurophysiological marker
arm group label: TRANSCRANIAL MAGNETIC STIMULATION
arm group type: Active Comparator
description: repetitive TRANSCRANIAL MAGNETIC STIMULATION (rTMS) will be applied over the precuneus to modulate DMN activity. The rTMS treatment will consist of two phases: an intensive phase and a maintenance phase. The intensive phase will involve 2 weeks of treatment, 5 days per week (10 sessions, 1.600 pulses per day for a total of 16.000 pulses). The maintenance phase will consist of 1 session of treatment every week for 5 months (21 sessions, 100.800 pulses in total).
arm group label: SHAM TRANSCRANIAL MAGNETIC STIMULATION
arm group type: Sham Comparator
description: SHAM TMS will be applied over the precuneus. The SHAM protocol will consist of two phases: an intensive phase and a maintenance phase. The intensive phase will involve 2 weeks of treatment, 5 days per week (10 sessions, 1.600 pulses per day for a total of 16.000 pulses). The maintenance phase will consist of 1 session of treatment every week for 5 months (21 sessions, 100.800 pulses in total).
intervention type: Device
intervention name: REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION
description: daily treatment session of REPETITIVE TRANSCRANIAL MAGNETIC STIMULATIO will be applied over precuneus for 20 minutes of consecutive blocks of 20Hz pulses for two seconds followed by 28 seconds of no stimulation.
arm group label: SHAM TRANSCRANIAL MAGNETIC STIMULATION
arm group label: TRANSCRANIAL MAGNETIC STIMULATION
other name: RTMS
criteria: 
gender: All
minimum age: 30 Years
maximum age: 85 Years
healthy volunteers: No
last name: Caterina Motta
role: Study Director
affiliation: Santa Lucia Foundation
facility: 
facility: 
country: Italy
citation: Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.
PMID: 29277405
citation: Di Lorenzo F, Ponzo V, Bonni S, Motta C, Negrao Serra PC, Bozzali M, Caltagirone C, Martorana A, Koch G. Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset. Ann Neurol. 2016 Aug;80(2):202-10. doi: 10.1002/ana.24695. Epub 2016 Jul 8.
PMID: 27255833
responsible party type: Principal Investigator
investigator affiliation: I.R.C.C.S. Fondazione Santa Lucia
investigator full name: Giacomo Koch
investigator title: Head of Laboratory
mesh term: Alzheimer Disease
sharing ipd: Undecided
ipd description: It is not yet known if there will be a plan to make IPD available.