<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/NCT03290326</url>
  </required_header>
  <id_info>
    <org_study_id>2017P000373</org_study_id>
    <nct_id>NCT03290326</nct_id>
  </id_info>
  <brief_title>tACS for Amyloid-β Reduction in Alzheimer's Disease</brief_title>
  <official_title>Feasibility and Safety of a High-Frequency Transcranial Alternating Current Stimulation Intervention for Amyloid-β Reduction in Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</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>
    <is_unapproved_device>Yes</is_unapproved_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated&#xD;
      tau (p-tau) in the brain, as well as widespread neurodegeneration. The evidence suggests that&#xD;
      both amyloid and tau play a critical role in AD and interventions that reliably and safely&#xD;
      decrease the intracerebral burden of amyloid or tau could potentially be of marked clinical&#xD;
      importance. Currently, therapeutic options are very limited and while there are pharmacologic&#xD;
      interventions that transiently improve cognitive function, there are no treatments that alter&#xD;
      disease progression. The current study seeks to use a novel therapeutic intervention that&#xD;
      uses noninvasive brain stimulation to target amyloid in the brain. The investigators&#xD;
      anticipate this will decrease the amyloid levels in the brain, as evidence by Positron&#xD;
      Emission Tomography (PET) imaging.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated&#xD;
      tau (p-tau) in the brain, as well as widespread neurodegeneration. There is no current&#xD;
      treatments that alter disease progression.&#xD;
&#xD;
      Investigators will recruit 20 individuals with AD with evidence of amyloid placques in the&#xD;
      brain through Positron Emission Tomography (PET) imaging. Investigators will use a novel&#xD;
      approach, transcranial alternating current stimulation (tACS), to target the region of&#xD;
      maximum amyloid burden in the brain. All participants will receive tACS. Each individual's&#xD;
      participation in the study will consist of approximately 16 visits: 3 days for&#xD;
      screening/baseline procedures as described below, 10 tACS study visits, and 3 days for&#xD;
      follow-up assessments. Subjects will undergo baseline cognitive assessment, structural and&#xD;
      functional MRI characterization, and resting-state EEG measurement. Additionally, patients&#xD;
      will undergo a tACS-EEG recording session to assess brain plasticity levels and identify&#xD;
      markers of response to stimulation. All subjects will then undergo 10 1-hour sessions of&#xD;
      gamma-frequency (40 Hz) tACS, targeted to the region of maximal tracer uptake on the amyloid&#xD;
      PET study. Subjects will take a standardized adverse effect questionnaire before and after&#xD;
      each session and complete a short cognitive test after each session to demonstrate safety and&#xD;
      tolerability. At the end of the 10 sessions, subjects will then repeat the baseline&#xD;
      assessments, followed by repeat amyloid PET imaging to assess for changes in amyloid burden.&#xD;
&#xD;
      Investigators anticipate that targeting the region of amyloid burden in the brain with tACS&#xD;
      will reduce the amyloid burden as evidence by the follow up PET imaging and show improvement&#xD;
      on electrophysiological measures of brain function and on cognitive testing. If our&#xD;
      prediction is correct, this will will provide a critical first step in the development of a&#xD;
      novel intervention to prevent and treat AD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 27, 2017</start_date>
  <completion_date type="Actual">May 14, 2019</completion_date>
  <primary_completion_date type="Actual">May 14, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Amyloid Burden</measure>
    <time_frame>Up to six weeks</time_frame>
    <description>Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 10 tACS sessions. The metric used is SUVR, a measure of the amount of proteins in the brain identified at the PET exam. We will calculate the difference between pre and post tACS SUVR (dSUVR) for the entire brain and report the average value (and standard deviation) for the entire group of patients. A negative value express a decrease in the amount of proteins in the brain post tACS intervention. It must be considered that dSUVR values refer to the entire brain, however patients were treated according to personalized tACS montages targeting patient-specific regions mostly affected by the pathology. This might have led to slightly different changes in SUVR in different part of the brain across participants. Also, as per standard procedures, results are presented at group level, i.e. without considering individual differences in longitudinal amyloid load changes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in EEG Gamma-band Spectral Power</measure>
    <time_frame>Up to six weeks</time_frame>
    <description>EEG power spectral densities (PSD) before and after the tACS intervention were evaluated, specifically absolute and relative power density values (μV2/Hz) were calculated within the gamma band (35-45Hz). Changes in the spectral power are reported in term of percentage of changes in relative spectral power from Pre to Post tACS intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Adas-Cog Score</measure>
    <time_frame>Up to six weeks</time_frame>
    <description>Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from a total score of 0-70 with higher score indicating greater cognitive impairment.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>tACS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays. The tACS intervention (10 sessions) will be preceded and followed by amyloid PET imaging as well as a clinical/cognitive evaluation. The assessment of adverse effects will constitute a Primary outcome measure. Changes in amyloid load in the stimulated brain region will be evaluated and constitute a secondary outcome of the study. Clinically relevant changes in cognitive and clinical scores will be also evaluated as secondary outcomes. Stimulation will be also preceded and followed by electroencephalography (EEG) recording aimed at assessing changes in spectral power in the gamma band.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial Alternating Current Stimulation (tACS)</intervention_name>
    <description>tACS will be applied at a frequency of 40Hz and targeting the area of maximal tracer uptake on amyloid PET imaging using an individualized multielectrode design to maximize the induced electrical current to the target region.</description>
    <arm_group_label>tACS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Clinical Diagnosis of mild AD defined by: Clinical Dementia Rating (CDR) = 0.5-1, Mini&#xD;
             Mental State Examination (MMSE) &gt;/= 20, Demonstration or history of memory impairments&#xD;
&#xD;
          -  Amyloid positive PET imaging&#xD;
&#xD;
          -  At least 45 years old&#xD;
&#xD;
          -  On a stable dose of medications for memory loss including cholinesterase inhibitors&#xD;
             (e.g. donepezil, rivastigmine or memantine) as defined as 6 consecutive weeks of&#xD;
             treatment at an unchanging dose&#xD;
&#xD;
          -  Intelligence Quotient (IQ) &gt; 85 as determined by the Wechsler Test of Adult Reading&#xD;
             (WTAR) and no history of intellectual disability&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current history of poorly controlled migraines including chronic medication for&#xD;
             migraine prevention&#xD;
&#xD;
          -  Current or past history of any neurological disorder other than dementia, such as&#xD;
             epilepsy, stroke, progressive neurologic disease (e.g. multiple sclerosis) or&#xD;
             intracranial brain lesions; and history of previous neurosurgery or head trauma that&#xD;
             resulted in residual neurologic impairment.&#xD;
&#xD;
          -  Past or current history of major depression, bipolar disorder or psychotic disorders,&#xD;
             or any other major psychiatric condition.&#xD;
&#xD;
          -  Contraindication for undergoing MRI or receiving Transcranial Magnetic Stimulation&#xD;
             (TMS) or tACS,&#xD;
&#xD;
             • History of fainting spells of unknown or undetermined etiology that might constitute&#xD;
             seizures.&#xD;
&#xD;
          -  History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG or&#xD;
             immediate (1st degree relative) family history of epilepsy; with the exception of a&#xD;
             single seizure of benign etiology (e.g. febrile seizure) in the judgment of the&#xD;
             investigator.&#xD;
&#xD;
          -  Chronic (particularly) uncontrolled medical conditions that may cause a medical&#xD;
             emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia,&#xD;
             asthma, etc.).&#xD;
&#xD;
          -  Metal implants (excluding dental fillings) or devices such as pacemaker, medication&#xD;
             pump, nerve stimulator, Transcutaneous Electrical Nerve Stimulator (TENS) unit,&#xD;
             ventriculo-peritoneal shunt, cochlear implant, unless cleared by the study MD.&#xD;
&#xD;
          -  Substance abuse or dependence within the past six months.&#xD;
&#xD;
          -  Medications will be reviewed by the responsible MD and a decision about inclusion will&#xD;
             be made based on the following: The patient's past medical history, drug dose, history&#xD;
             of recent medication changes or duration of treatment, and combination of Central&#xD;
             Nervous System (CNS) active drugs.&#xD;
&#xD;
          -  All female participants that are pre-menopausal will be required to have a pregnancy&#xD;
             test; any participant who is pregnant will not be enrolled in the study.&#xD;
&#xD;
          -  BMI &gt; 40 kg/m2. We will limit the BMI to &lt;40 kg/m2 because of weight limits of the&#xD;
             scanner bed and width limits of the MRI.&#xD;
&#xD;
          -  Subjects who, in the investigator's opinion, might not be suitable for the study&#xD;
&#xD;
          -  A hair style or head dress that prevents electrode contact with the scalp or would&#xD;
             interfere with the stimulation (for example: thick braids, hair weave, afro, wig)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Emiliano Santarnecchi</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>September 15, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <results_first_submitted>July 20, 2020</results_first_submitted>
  <results_first_submitted_qc>March 1, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 3, 2022</results_first_posted>
  <last_update_submitted>August 18, 2022</last_update_submitted>
  <last_update_submitted_qc>August 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Emiliano Santarnecchi</investigator_full_name>
    <investigator_title>Associate Professor of Radiology</investigator_title>
  </responsible_party>
  <keyword>Alzheimer</keyword>
  <keyword>Memory Problems</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 15, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/26/NCT03290326/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Of 17 enrolled participants, 10 met inclusion criteria and underwent transcranial alternating current stimulation (tACS)</recruitment_details>
      <pre_assignment_details>During the screening and baseline procedures 7 participants screened out for the following reasons: 4 participants screened out on cognitive testing measures, being either too advanced or too mild, 2 participants did not meet 6 weeks stable medication inclusion criteria, and 1 participant screened out due to incidental findings on the baseline MRI</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>tACS</title>
          <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) was applied for 1 hour in 10 sessions on consecutive weekdays.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>tACS</title>
          <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) was applied for 1 hour in 10 sessions on consecutive weekdays.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Age</title>
              <category_list>
                <category>
                  <title>55</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>57</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>63</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>75</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>76</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>78</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>79</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>83</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Amyloid Burden</title>
        <description>Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 10 tACS sessions. The metric used is SUVR, a measure of the amount of proteins in the brain identified at the PET exam. We will calculate the difference between pre and post tACS SUVR (dSUVR) for the entire brain and report the average value (and standard deviation) for the entire group of patients. A negative value express a decrease in the amount of proteins in the brain post tACS intervention. It must be considered that dSUVR values refer to the entire brain, however patients were treated according to personalized tACS montages targeting patient-specific regions mostly affected by the pathology. This might have led to slightly different changes in SUVR in different part of the brain across participants. Also, as per standard procedures, results are presented at group level, i.e. without considering individual differences in longitudinal amyloid load changes.</description>
        <time_frame>Up to six weeks</time_frame>
        <population>Mild to Moderate Alzheimer's Disease patients</population>
        <group_list>
          <group group_id="O1">
            <title>tACS</title>
            <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays. The tACS intervention (10 sessions) will be preceded and followed by amyloid PET imaging as well as a clinical/cognitive evaluation. The assessment of adverse effects will constitute a Primary outcome measure. Changes in amyloid load in the stimulated brain region will be evaluated and constitute a secondary outcome of the study. Clinically relevant changes in cognitive and clinical scores will be also evaluated as secondary outcomes. Stimulation will be also preceded and followed by electroencephalography (EEG) recording aimed at assessing changes in spectral power in the gamma band.&#xD;
tACS will be applied at a frequency of 40Hz and targeting the area of maximal tracer uptake on amyloid PET imaging using an individualized multielectrode design to maximize the induced electrical current to the target region.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Amyloid Burden</title>
          <description>Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 10 tACS sessions. The metric used is SUVR, a measure of the amount of proteins in the brain identified at the PET exam. We will calculate the difference between pre and post tACS SUVR (dSUVR) for the entire brain and report the average value (and standard deviation) for the entire group of patients. A negative value express a decrease in the amount of proteins in the brain post tACS intervention. It must be considered that dSUVR values refer to the entire brain, however patients were treated according to personalized tACS montages targeting patient-specific regions mostly affected by the pathology. This might have led to slightly different changes in SUVR in different part of the brain across participants. Also, as per standard procedures, results are presented at group level, i.e. without considering individual differences in longitudinal amyloid load changes.</description>
          <population>Mild to Moderate Alzheimer's Disease patients</population>
          <units>dSUVR</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.55" spread="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in EEG Gamma-band Spectral Power</title>
        <description>EEG power spectral densities (PSD) before and after the tACS intervention were evaluated, specifically absolute and relative power density values (μV2/Hz) were calculated within the gamma band (35-45Hz). Changes in the spectral power are reported in term of percentage of changes in relative spectral power from Pre to Post tACS intervention.</description>
        <time_frame>Up to six weeks</time_frame>
        <population>The assessment of the effect of 40 Hz tACS on EEG gamma-band spectral power.</population>
        <group_list>
          <group group_id="O1">
            <title>tACS 40Hz</title>
            <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays. The tACS intervention (10 sessions) will be preceded and followed by amyloid, microglia and tau PET imaging as well as a clinical/cognitive evaluation. The assessment of the effect of stimulation on microglia activation, amyloid deposition and tau deposition will constitute a primary outcome measure. Assessment of adverse effects will be also evaluated as a secondary outcome. The effect of brain stimulation on brain connectivity will be assessed by EEG and cognitive function.&#xD;
Transcranial Alternating Current Stimulation (tACS): tACS will be applied at a frequency of 40Hz and targeting the area of maximal tracer uptake on amyloid PET imaging using an individualized multielectrode design to maximize the induced electrical current to the target region.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in EEG Gamma-band Spectral Power</title>
          <description>EEG power spectral densities (PSD) before and after the tACS intervention were evaluated, specifically absolute and relative power density values (μV2/Hz) were calculated within the gamma band (35-45Hz). Changes in the spectral power are reported in term of percentage of changes in relative spectral power from Pre to Post tACS intervention.</description>
          <population>The assessment of the effect of 40 Hz tACS on EEG gamma-band spectral power.</population>
          <units>% difference in spectral power (μV2/Hz)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.5" spread="13.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>One-way ANOVA was conducted to compare the effect of 40Hz tACS on EEG gamma-band spectral power. Power changes were expressed as percentage relative power variations, accordingly with the event-related synchronization/desynchronization (ERS/ERD) index.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt; 0.01</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Adas-Cog Score</title>
        <description>Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from a total score of 0-70 with higher score indicating greater cognitive impairment.</description>
        <time_frame>Up to six weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>tACS</title>
            <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Adas-Cog Score</title>
          <description>Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from a total score of 0-70 with higher score indicating greater cognitive impairment.</description>
          <units>Scores on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.97" spread="3.88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>5 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>tACS</title>
          <description>Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Scalp Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neck Pain</sub_title>
                <description>related to TMS positioning</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin Irritation</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sensations under electrodes</sub_title>
                <description>tingling, burning, itching</description>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Visual Changes</sub_title>
                <description>flashing lights in peripheral vision</description>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nervousness</sub_title>
                <description>related to cognitive testing</description>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Difficulty concentrating</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hand tingling</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Principal Investigator - Emiliano Santarnecchi</name_or_title>
      <organization>BIDMC</organization>
      <phone>617-667-0326</phone>
      <email>esantarn@bidmc.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03290326
org study id: 2017P000373
nct id: NCT03290326
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is unapproved device: Yes
is us export: No
Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated
      tau (p-tau) in the brain, as well as widespread neurodegeneration. The evidence suggests that
      both amyloid and tau play a critical role in AD and interventions that reliably and safely
      decrease the intracerebral burden of amyloid or tau could potentially be of marked clinical
      importance. Currently, therapeutic options are very limited and while there are pharmacologic
      interventions that transiently improve cognitive function, there are no treatments that alter
      disease progression. The current study seeks to use a novel therapeutic intervention that
      uses noninvasive brain stimulation to target amyloid in the brain. The investigators
      anticipate this will decrease the amyloid levels in the brain, as evidence by Positron
      Emission Tomography (PET) imaging.
Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated
      tau (p-tau) in the brain, as well as widespread neurodegeneration. There is no current
      treatments that alter disease progression.

      Investigators will recruit 20 individuals with AD with evidence of amyloid placques in the
      brain through Positron Emission Tomography (PET) imaging. Investigators will use a novel
      approach, transcranial alternating current stimulation (tACS), to target the region of
      maximum amyloid burden in the brain. All participants will receive tACS. Each individual's
      participation in the study will consist of approximately 16 visits: 3 days for
      screening/baseline procedures as described below, 10 tACS study visits, and 3 days for
      follow-up assessments. Subjects will undergo baseline cognitive assessment, structural and
      functional MRI characterization, and resting-state EEG measurement. Additionally, patients
      will undergo a tACS-EEG recording session to assess brain plasticity levels and identify
      markers of response to stimulation. All subjects will then undergo 10 1-hour sessions of
      gamma-frequency (40 Hz) tACS, targeted to the region of maximal tracer uptake on the amyloid
      PET study. Subjects will take a standardized adverse effect questionnaire before and after
      each session and complete a short cognitive test after each session to demonstrate safety and
      tolerability. At the end of the 10 sessions, subjects will then repeat the baseline
      assessments, followed by repeat amyloid PET imaging to assess for changes in amyloid burden.

      Investigators anticipate that targeting the region of amyloid burden in the brain with tACS
      will reduce the amyloid burden as evidence by the follow up PET imaging and show improvement
      on electrophysiological measures of brain function and on cognitive testing. If our
      prediction is correct, this will will provide a critical first step in the development of a
      novel intervention to prevent and treat AD.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Amyloid Burden
time frame: Up to six weeks
description: Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 10 tACS sessions. The metric used is SUVR, a measure of the amount of proteins in the brain identified at the PET exam. We will calculate the difference between pre and post tACS SUVR (dSUVR) for the entire brain and report the average value (and standard deviation) for the entire group of patients. A negative value express a decrease in the amount of proteins in the brain post tACS intervention. It must be considered that dSUVR values refer to the entire brain, however patients were treated according to personalized tACS montages targeting patient-specific regions mostly affected by the pathology. This might have led to slightly different changes in SUVR in different part of the brain across participants. Also, as per standard procedures, results are presented at group level, i.e. without considering individual differences in longitudinal amyloid load changes.
measure: Change in EEG Gamma-band Spectral Power
time frame: Up to six weeks
description: EEG power spectral densities (PSD) before and after the tACS intervention were evaluated, specifically absolute and relative power density values (μV2/Hz) were calculated within the gamma band (35-45Hz). Changes in the spectral power are reported in term of percentage of changes in relative spectral power from Pre to Post tACS intervention.
measure: Change in Adas-Cog Score
time frame: Up to six weeks
description: Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from a total score of 0-70 with higher score indicating greater cognitive impairment.
arm group label: tACS
arm group type: Experimental
description: Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays. The tACS intervention (10 sessions) will be preceded and followed by amyloid PET imaging as well as a clinical/cognitive evaluation. The assessment of adverse effects will constitute a Primary outcome measure. Changes in amyloid load in the stimulated brain region will be evaluated and constitute a secondary outcome of the study. Clinically relevant changes in cognitive and clinical scores will be also evaluated as secondary outcomes. Stimulation will be also preceded and followed by electroencephalography (EEG) recording aimed at assessing changes in spectral power in the gamma band.
intervention type: Device
intervention name: Transcranial Alternating Current Stimulation (tACS)
description: tACS will be applied at a frequency of 40Hz and targeting the area of maximal tracer uptake on amyloid PET imaging using an individualized multielectrode design to maximize the induced electrical current to the target region.
arm group label: tACS
criteria: 
gender: All
minimum age: 45 Years
maximum age: N/A
healthy volunteers: No
last name: Emiliano Santarnecchi
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Emiliano Santarnecchi
investigator title: Associate Professor of Radiology
mesh term: Alzheimer Disease
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 