<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/NCT03270137</url>
  </required_header>
  <id_info>
    <org_study_id>SIC-16-001</org_study_id>
    <nct_id>NCT03270137</nct_id>
  </id_info>
  <brief_title>Repetitive Transcranial Magnetic Stimulation in Patients With Alzheimer Disease</brief_title>
  <acronym>AD-EMTr</acronym>
  <official_title>Cognitive, Behavioral and Functional Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) in Patients With Potential Alzheimer Disease: Two Treatment Modalities Comparison</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Nacional de Psiquiatría Dr. Ramón de la Fuente</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Council of Science and Technology, Mexico</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Instituto Nacional de Psiquiatría Dr. Ramón de la Fuente</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>
      Randomized clinical trial, comparative and single blind aims to determine effects on&#xD;
      cognition, psychological and behavioral symptoms and functionality of 5 Hz repetitive&#xD;
      transcranial magnetic stimulation (rTMS) administered over left dorsolateral prefrontal&#xD;
      cortex (lDLPFC) compared to six regions protocol, divided in two sub-conditions: day 1 (Broca&#xD;
      area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association&#xD;
      cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated&#xD;
      at ending of 15 rTMS sessions and 4 weeks after.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive&#xD;
      decline that affects behavior and daily functionality. Its etiology is unknown and treatment&#xD;
      efficacy is partial. Repetitive transcranial magnetic stimulation has been suggested as a&#xD;
      potential treatment as of several trials has revealed improvements in language, episodic&#xD;
      memory, psychological and behavioral symptoms in dementia as well as functionality using&#xD;
      different experimental designs, stimulation parameters and cortical targets comparisons.&#xD;
      However, it remains to determine the most effective modality, comparing outcomes with&#xD;
      cortical targets poorly studied and how much the effects last. The main objective of this&#xD;
      study is to determine which of two stimulation modalities provides a better cognitive and&#xD;
      behavioral effect also on functionality in patients with potential diagnosis of AD,&#xD;
      administered over lDLPFC (Condition A) and a six areas condition (Condition B) in which are&#xD;
      alternated two sub-conditions (Day 1: Broca and Wernicke areas and lDLPFC, and Day 2:&#xD;
      bilateral parietal association cortex and rDLPFC) along 15 sessions and 1500 pulses per&#xD;
      session.&#xD;
&#xD;
      For this purpose, will be randomized 22 patients with potential diagnosis of AD (according to&#xD;
      DSM-5) to both stimulation conditions (11 patients to each condition). The rTMS will be&#xD;
      administered at 5 Hz and 1500 pulses per session (30 trains and 10 seconds inter-train&#xD;
      interval) along 15 sessions with a post-treatment evaluation at 4 weeks comparing: time&#xD;
      response, post-treatment effects and 4 weeks effects.&#xD;
&#xD;
      To evaluate clinical response among stimulation conditions will be used Alzheimer´s Disease&#xD;
      Assessment Scale COGNITIVE (ADAS-cog), Cumming's Neuropsychiatric Inventory (NPI), Yesavage&#xD;
      Geriatric Depression Scale (GDS), Interview for Deterioration-in-daily Living Activities in&#xD;
      Dementia (IDDD) and Clinical Global Impression (CGI). The modified version of Mini Mental&#xD;
      State (MMSE-FOLSTEIN) will be applied in the same time points of other evaluations also at&#xD;
      the session 5 and 10. Other interest variables are: age, sex, civil status, education,&#xD;
      occupation, time and type of pharmacological treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">March 10, 2016</start_date>
  <completion_date type="Anticipated">August 31, 2017</completion_date>
  <primary_completion_date type="Actual">February 28, 2017</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>Parallel Assignment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
    <masking_description>Single Blind (Investigator)</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Changes on cognitive functioning (ADAS-cog)</measure>
    <time_frame>Baseline, Post rTMS treatment: at week 3, and at week 4.</time_frame>
    <description>ADAS-cog is cognitive testing instrument to measure severity. It explores 11 domains including memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes on cognitive effects (Mini Mental State)</measure>
    <time_frame>Baseline, every week for 3 weeks during rTMS treatment and at the 4th week after treatment.</time_frame>
    <description>This instrument gives scores to orientation in time and space, registration information (three words) and recovering, attention, calculation, language (denomination, repetition, understanding of complex orders, reading and writing) and finally visuoconstruction (two overlapping diamonds).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on behavioral symptoms (NPI)</measure>
    <time_frame>Baseline, Post rTMS treatment: at week 3, and at week 4.</time_frame>
    <description>This is a diagnostic instrument to determine the presence of behavioral symptoms. It measures frequency and severity of symptoms in the last month and the overload for the caregiver. This test divides behavioral symptoms in: delirium, hallucinations, agitation or aggressivity, anxiety, euphoria, apathy, irritability/lability, disinhibition, aberrant motor behavior, sleep and appetite/feeding.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on depression symptoms (GDS-Yesavage)</measure>
    <time_frame>Baseline, Post rTMS treatment: at week 3, and at week 4.</time_frame>
    <description>Repeated application allows to evaluate changes in the geriatric depression evolution.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on effects on functionality (IDDD)</measure>
    <time_frame>Baseline, Post rTMS treatment: at week 3, and at week 4.</time_frame>
    <description>This is an instrument designed to evaluate functionality in dementia. It evaluates self-care and complex activities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on Clinical Global Impression (CGI)</measure>
    <time_frame>Baseline, Post rTMS treatment: at week 3, and at week 4.</time_frame>
    <description>Standardized and descriptive scale, it gives qualitative information to identify changes in the illness through measuring severity of clinical picture and improvements triggered by treatments (change in the time) as well as treatment efficacy.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Alzheimer Disease</condition>
  <condition>Transcranial Magnetic Stimulation</condition>
  <arm_group>
    <arm_group_label>Condition A: rTMS on L-DLPFC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Repetitive transcranial magnetic stimulation- IDLPFC. The intervention will be rTMS delivered on left dorsolateral prefrontal cortex (L-DLPFC).&#xD;
Every patient will receive 15 rTMS sessions (in weekdays) along three weeks at 5 Hz of frequency and at its 100% of motor threshold. Each session will consist of 30 trains separated by 10 seconds inter-train interval and 1500 total pulses per session.&#xD;
Equipment to rTMS includes a Magpro R30 stimulator (Magventure, Denmark) with an 8-shape coil model MCF-B70.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Condition B: rTMS on six regions</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Repetitive transcranial magnetic stimulation - Six regions. Two sub-conditions will alternate each session, starting with day 1: rTMS on Broca and Wernicke area and lDLPFC and then day 2: rTMS on left and right parietal association cortex (lPAC; rPAC) and right dorsolateral prefrontal cortex (rDLPFC).&#xD;
Patients will receive 15 intervention sessions (in weekdays) along three weeks at 5 Hz frequency and 100% of motor threshold. Each area will receive 10 trains (500 pulses) separated by 10 seconds of inter-train interval that correspond to 1500 total pulses per session.&#xD;
Equipment to rTMS includes a Magpro stimulator (Dantec, Denmark) with an 8-shape coil model MC-B70.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>repetitive transcranial magnetic stimulation- IDLPFC</intervention_name>
    <description>Repetitive transcranial magnetic stimulation (rTMS) at 5Hz administered over left dorsolateral prefrontal cortex (lDLPFC). Repetitive transcranial magnetic stimulation (rTMS) at 5Hz administered over left dorsolateral prefrontal cortex (lDLPFC) compared to six regions protocol, divided in two sub-conditions: day 1 (Broca area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated at ending of 15 rTMS sessions and 4 weeks after.</description>
    <arm_group_label>Condition A: rTMS on L-DLPFC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>repetitive transcranial magnetic stimulation - Six regions</intervention_name>
    <description>Repetitive transcranial magnetic stimulation (rTMS) at 5Hz administered on six regions protocol, divided in two sub-conditions: day 1 (Broca area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated at ending of 15 rTMS sessions and 4 weeks after.</description>
    <arm_group_label>Condition B: rTMS on six regions</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with file number at National Institute of Psychiatry &quot;Ramón de la Fuente&#xD;
             Muñiz&quot;.&#xD;
&#xD;
          -  Scholarship of at least 5 years or above.&#xD;
&#xD;
          -  Dementia diagnosis established by clinical examination made by their responsible&#xD;
             physician, according the Diagnose Criteria for Alzheimer Disease for possible, mild or&#xD;
             moderate according to DSM-5. Severity will be stratified with Mini-Mental State&#xD;
             (MMSE-FOLSTEIN): as a) mild: 21-26 and b) moderated 15-20 points; in addition, with&#xD;
             Reisberg Global Deterioration, the states from 2 to 4 that correspond a cognitive&#xD;
             deficit mild and moderated.&#xD;
&#xD;
          -  In the case of concomitant treatment with memantine or acetylcholinesterase&#xD;
             inhibitors, the patient should have taken it for at least 6 months prior to study.&#xD;
&#xD;
          -  In the case of other pharmacological treatments for psychiatric conditions, for&#xD;
             example, antidepressants, anxiolytic or antipsychotics, the patient should have taken&#xD;
             stable doses for at least 2 months.&#xD;
&#xD;
          -  Patients with another no-psychiatric comorbidity should be stable (according to&#xD;
             diagnostic criteria and supported by laboratory studies or metric assessments).&#xD;
&#xD;
          -  Every patient should have a caregiver (for example, spouse, a relative or a&#xD;
             professional caregiver) along the study who could stay with the patient at least 10&#xD;
             hours/week.&#xD;
&#xD;
          -  Signing of informed consent by patient and caregiver.&#xD;
&#xD;
          -  Patients and caregivers who can attend in weekdays, along three weeks assessments and&#xD;
             treatment sessions at National Institute of Psychiatry &quot;Ramón de la Fuente Muñiz&quot;.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with severe agitation symptoms or difficulties to cooperate with the study.&#xD;
&#xD;
          -  Patients with history of epilepsy.&#xD;
&#xD;
          -  Patients with sudden onset of apoplexy, focal neurologic findings as hemiparesis,&#xD;
             sensory loss, visual field deficit and lack of coordination in the legs in early&#xD;
             stages of disease.&#xD;
&#xD;
          -  Convulsion or walking disorder at onset or very early stages of the disease.&#xD;
&#xD;
          -  Patients with history of severe psychiatric disorders.&#xD;
&#xD;
          -  Patients with alterations in a conventional electroencephalogram (paroxysmal phenomena&#xD;
             identified by a specialized clinical neurophysiologist).&#xD;
&#xD;
          -  Patients with pacemaker or implanted metallic intracranial objects.&#xD;
&#xD;
        Elimination criteria:&#xD;
&#xD;
          -  Decision of patient or caregiver to left the study.&#xD;
&#xD;
          -  Modification in doses or pharmacological treatment prior to start the study.&#xD;
&#xD;
          -  Patients with new clinical findings and who require complementary pharmacological&#xD;
             treatment.&#xD;
&#xD;
          -  Presence of adverse events that could affect health and could limit maintain the&#xD;
             patient in treatment.&#xD;
&#xD;
          -  Exacerbation of cognitive or behavioral symptoms during the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 21, 2017</study_first_submitted>
  <study_first_submitted_qc>August 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 1, 2017</study_first_posted>
  <last_update_submitted>August 31, 2017</last_update_submitted>
  <last_update_submitted_qc>August 31, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Instituto Nacional de Psiquiatría Dr. Ramón de la Fuente</investigator_affiliation>
    <investigator_full_name>Ruth Alcala Lozano</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Alzheimer Disease</keyword>
  <keyword>rTMS</keyword>
  <keyword>Cognition</keyword>
  <keyword>Behavioral Symptoms</keyword>
  <keyword>Functionality</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>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>April 2, 2020</submitted>
    <returned>April 14, 2020</returned>
    <submitted>December 3, 2020</submitted>
    <returned>December 28, 2020</returned>
  </pending_results>
  <!-- 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/NCT03270137
org study id: SIC-16-001
nct id: NCT03270137
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Randomized clinical trial, comparative and single blind aims to determine effects on
      cognition, psychological and behavioral symptoms and functionality of 5 Hz repetitive
      transcranial magnetic stimulation (rTMS) administered over left dorsolateral prefrontal
      cortex (lDLPFC) compared to six regions protocol, divided in two sub-conditions: day 1 (Broca
      area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association
      cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated
      at ending of 15 rTMS sessions and 4 weeks after.
Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive
      decline that affects behavior and daily functionality. Its etiology is unknown and treatment
      efficacy is partial. Repetitive transcranial magnetic stimulation has been suggested as a
      potential treatment as of several trials has revealed improvements in language, episodic
      memory, psychological and behavioral symptoms in dementia as well as functionality using
      different experimental designs, stimulation parameters and cortical targets comparisons.
      However, it remains to determine the most effective modality, comparing outcomes with
      cortical targets poorly studied and how much the effects last. The main objective of this
      study is to determine which of two stimulation modalities provides a better cognitive and
      behavioral effect also on functionality in patients with potential diagnosis of AD,
      administered over lDLPFC (Condition A) and a six areas condition (Condition B) in which are
      alternated two sub-conditions (Day 1: Broca and Wernicke areas and lDLPFC, and Day 2:
      bilateral parietal association cortex and rDLPFC) along 15 sessions and 1500 pulses per
      session.

      For this purpose, will be randomized 22 patients with potential diagnosis of AD (according to
      DSM-5) to both stimulation conditions (11 patients to each condition). The rTMS will be
      administered at 5 Hz and 1500 pulses per session (30 trains and 10 seconds inter-train
      interval) along 15 sessions with a post-treatment evaluation at 4 weeks comparing: time
      response, post-treatment effects and 4 weeks effects.

      To evaluate clinical response among stimulation conditions will be used Alzheimer´s Disease
      Assessment Scale COGNITIVE (ADAS-cog), Cumming's Neuropsychiatric Inventory (NPI), Yesavage
      Geriatric Depression Scale (GDS), Interview for Deterioration-in-daily Living Activities in
      Dementia (IDDD) and Clinical Global Impression (CGI). The modified version of Mini Mental
      State (MMSE-FOLSTEIN) will be applied in the same time points of other evaluations also at
      the session 5 and 10. Other interest variables are: age, sex, civil status, education,
      occupation, time and type of pharmacological treatment.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Parallel Assignment
primary purpose: Treatment
masking: Single (Investigator)
masking description: Single Blind (Investigator)
measure: Changes on cognitive functioning (ADAS-cog)
time frame: Baseline, Post rTMS treatment: at week 3, and at week 4.
description: ADAS-cog is cognitive testing instrument to measure severity. It explores 11 domains including memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD.
measure: Changes on cognitive effects (Mini Mental State)
time frame: Baseline, every week for 3 weeks during rTMS treatment and at the 4th week after treatment.
description: This instrument gives scores to orientation in time and space, registration information (three words) and recovering, attention, calculation, language (denomination, repetition, understanding of complex orders, reading and writing) and finally visuoconstruction (two overlapping diamonds).
measure: Changes on behavioral symptoms (NPI)
time frame: Baseline, Post rTMS treatment: at week 3, and at week 4.
description: This is a diagnostic instrument to determine the presence of behavioral symptoms. It measures frequency and severity of symptoms in the last month and the overload for the caregiver. This test divides behavioral symptoms in: delirium, hallucinations, agitation or aggressivity, anxiety, euphoria, apathy, irritability/lability, disinhibition, aberrant motor behavior, sleep and appetite/feeding.
measure: Changes on depression symptoms (GDS-Yesavage)
time frame: Baseline, Post rTMS treatment: at week 3, and at week 4.
description: Repeated application allows to evaluate changes in the geriatric depression evolution.
measure: Changes on effects on functionality (IDDD)
time frame: Baseline, Post rTMS treatment: at week 3, and at week 4.
description: This is an instrument designed to evaluate functionality in dementia. It evaluates self-care and complex activities.
measure: Changes on Clinical Global Impression (CGI)
time frame: Baseline, Post rTMS treatment: at week 3, and at week 4.
description: Standardized and descriptive scale, it gives qualitative information to identify changes in the illness through measuring severity of clinical picture and improvements triggered by treatments (change in the time) as well as treatment efficacy.
arm group label: Condition A: rTMS on L-DLPFC
arm group type: Active Comparator
description: Repetitive transcranial magnetic stimulation- IDLPFC. The intervention will be rTMS delivered on left dorsolateral prefrontal cortex (L-DLPFC).
Every patient will receive 15 rTMS sessions (in weekdays) along three weeks at 5 Hz of frequency and at its 100% of motor threshold. Each session will consist of 30 trains separated by 10 seconds inter-train interval and 1500 total pulses per session.
Equipment to rTMS includes a Magpro R30 stimulator (Magventure, Denmark) with an 8-shape coil model MCF-B70.
arm group label: Condition B: rTMS on six regions
arm group type: Active Comparator
description: Repetitive transcranial magnetic stimulation - Six regions. Two sub-conditions will alternate each session, starting with day 1: rTMS on Broca and Wernicke area and lDLPFC and then day 2: rTMS on left and right parietal association cortex (lPAC; rPAC) and right dorsolateral prefrontal cortex (rDLPFC).
Patients will receive 15 intervention sessions (in weekdays) along three weeks at 5 Hz frequency and 100% of motor threshold. Each area will receive 10 trains (500 pulses) separated by 10 seconds of inter-train interval that correspond to 1500 total pulses per session.
Equipment to rTMS includes a Magpro stimulator (Dantec, Denmark) with an 8-shape coil model MC-B70.
intervention type: Device
intervention name: repetitive transcranial magnetic stimulation- IDLPFC
description: Repetitive transcranial magnetic stimulation (rTMS) at 5Hz administered over left dorsolateral prefrontal cortex (lDLPFC). Repetitive transcranial magnetic stimulation (rTMS) at 5Hz administered over left dorsolateral prefrontal cortex (lDLPFC) compared to six regions protocol, divided in two sub-conditions: day 1 (Broca area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated at ending of 15 rTMS sessions and 4 weeks after.
arm group label: Condition A: rTMS on L-DLPFC
intervention type: Device
intervention name: repetitive transcranial magnetic stimulation - Six regions
description: Repetitive transcranial magnetic stimulation (rTMS) at 5Hz administered on six regions protocol, divided in two sub-conditions: day 1 (Broca area, Wernicke area and lDLPFC) alternated by day 2 (left and right parietal association cortex, and right dorsolateral prefrontal cortex [rDLPFC]). Main outcomes will be evaluated at ending of 15 rTMS sessions and 4 weeks after.
arm group label: Condition B: rTMS on six regions
criteria: 
gender: All
minimum age: 60 Years
maximum age: 85 Years
healthy volunteers: No
responsible party type: Principal Investigator
investigator affiliation: Instituto Nacional de Psiquiatría Dr. Ramón de la Fuente
investigator full name: Ruth Alcala Lozano
investigator title: Principal Investigator
mesh term: Alzheimer Disease
sharing ipd: Undecided
submitted: April 2, 2020
returned: April 14, 2020
submitted: December 3, 2020
returned: December 28, 2020