<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/NCT03025529</url>
  </required_header>
  <id_info>
    <org_study_id>2015P000011</org_study_id>
    <nct_id>NCT03025529</nct_id>
  </id_info>
  <brief_title>Transcranial Stimulation for Essential Tremor</brief_title>
  <official_title>Transcranial Stimulation for Essential Tremor</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Beth Israel Deaconess Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main purpose of this study is to see if transcranial magnetic stimulation (TMS) can be&#xD;
      used to help study brain function in healthy people and in those with neurological diseases&#xD;
      like essential tremor. This portion of the study is being done to establish the optimal&#xD;
      methods for stimulating the brain to measure its responses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Essential tremor (ET) is a movement disorder characterized by tremor of both hands, and often&#xD;
      head and voice, affecting approximately 4.8-6.7 million individuals over the age of 40 in the&#xD;
      United States alone. Hand tremor can limit basic activities of daily living like feeding,&#xD;
      drinking, writing and dressing. While medications can be effective for tremor, they are often&#xD;
      poorly tolerated due to their sedative or neuronal activity depressant properties. Surgical&#xD;
      options such as deep brain stimulation of the ventral intermedius thalamus (Vim DBS) can be&#xD;
      highly effective but its invasive nature limits its popularity. Noninvasive brain stimulation&#xD;
      has demonstrated the ability to reduce tremor but precisely where to target brain stimulation&#xD;
      to achieve the best results is currently unknown.&#xD;
&#xD;
      Repetitive transcranial magnetic stimulation (rTMS) enables noninvasive, selective and&#xD;
      sustained modulation of specific neural networks, and can lead to clinical benefits in&#xD;
      debilitating neurologic and psychiatric disorders, including medication-resistant depression,&#xD;
      paresis following stroke or traumatic brain injury, Parkinson's disease, or dementia. There&#xD;
      is also recent evidence that rTMS of the cerebellum can relieve hand tremor due to essential&#xD;
      tremor. TMS uses electromagnetic induction to generate controlled currents in targeted brain&#xD;
      structures that can be identified and defined using MRI-based neuronavigation. TMS is safe if&#xD;
      appropriate guidelines are adhered to. To date, the impact of rTMS on ET has not been&#xD;
      sufficiently established, but pilot studies offer promising results.&#xD;
&#xD;
      The investigators are testing whether MRI-guided neuronavigated cerebellar paired pulse TMS&#xD;
      demonstrates abnormal physiologic measures in ET subjects compared to controls and whether&#xD;
      there is reduction of tremor via cerebellar rTMS in patients with ET. The investigators plan&#xD;
      to collect imaging, functional and neurophysiological assessments before and after the rTMS&#xD;
      to identify the mechanistic underpinnings of rTMS-induced changes in tremor and&#xD;
      cerebello-cortical inhibition.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Investigator leaving institution&#xD;
  </why_stopped>
  <start_date>February 2015</start_date>
  <completion_date type="Actual">November 28, 2016</completion_date>
  <primary_completion_date type="Actual">November 28, 2016</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>Crossover Assignment</intervention_model>
    <intervention_model_description>This is a crossover design with two groups, preceded by a separate single group of healthy controls in a pilot study to assess feasibility of obtaining the cerebellocortical inhibition measure</intervention_model_description>
    <primary_purpose>Device Feasibility</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>In the single group pilot study, there is no intervention and no masking-- just obtaining an MRI and a cerebellocortical inhibition measure. There were 8 subjects in this phase of the study. There were no subjects enrolled in the crossover design phase of this study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Tremor Reduction</measure>
    <time_frame>One week after intervention</time_frame>
    <description>tremor rating scale with questions regarding impact of tremor on activities of daily living and an physician-rated assessment of degree of tremor in hands, head, voice, and while drawing and writing</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cerebellocortical Inhibition</measure>
    <time_frame>One week after intervention</time_frame>
    <description>Ratio of conditioned to unconditioned motor evoked potentials</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Essential Tremor</condition>
  <arm_group>
    <arm_group_label>Active Cerebellar rTMS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cerebellar rTMS will be carried out in ET subjects using a MagPro stimulator with a double cone coil at 1Hz (1 pulse every second) for 3 minutes on the left and 3 minutes on the right, at the cerebellar location indicated by resting state functional connectivity MRI analysis. Subjects with ET will undergo 5 consecutive daily sessions of cerebellar rTMS at either the connectivity map generated target or sham rTMS and then crossover to the other target after 2 weeks. Subjects will be blinded to the treatment order assignment. The intensity of the stimulation will be determined as 90% of the resting motor threshold, to be determined at the beginning of the first visit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham Cerebellar rTMS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>In sham rTMS, the same parameters and procedures as Treatment Procedures 4-8 will be used, except that the coil will be angled 90 degrees from the scalp, resting on one wing of the coil.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy control pilot</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>This pilot phase is done to assess feasibility of obtaining MRI and cerebellocortical inhibition measures in healthy control subjects.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial Magnetic Stimulation</intervention_name>
    <description>Transcranial Magnetic Stimulation or TMS is a noninvasive procedure (meaning it does not enter the body) that is used to stimulate a part of the brain using a magnetic field. This magnetic field can pass through the head safely and painlessly. TMS can be used to change activity in the brain.</description>
    <arm_group_label>Active Cerebellar rTMS</arm_group_label>
    <other_name>TMS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham Transcranial Magnetic Stimulation</intervention_name>
    <description>Sham Transcranial Magnetic Stimulation or sham TMS is like active TMS, a noninvasive procedure (meaning it does not enter the body) that is used to stimulate a part of the brain using a magnetic field. TMS can be used to change activity in the brain but in this intervention, the coil will be angled 90 degrees from the scalp, resting on one wing of the coil, and therefore will not be delivering active TMS.</description>
    <arm_group_label>Sham Cerebellar rTMS</arm_group_label>
    <other_name>Sham TMS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for ET subjects:&#xD;
&#xD;
          1. Outpatients with essential tremor as diagnosed and confirmed by movement disorder&#xD;
             specialist&#xD;
&#xD;
          2. Women of child-bearing potential must provide a negative pregnancy test at entry into&#xD;
             the study&#xD;
&#xD;
          3. Stable doses of all medications for at least 14 days prior to study entry and for the&#xD;
             duration of the study,&#xD;
&#xD;
          4. At least a 1cm amplitude tremor as judged by the screener using a ruler&#xD;
&#xD;
        Inclusion Criteria for Healthy Volunteers:&#xD;
&#xD;
          1. Healthy subjects without tremor and without significant neurologic disease suggestive&#xD;
             of cerebellar ataxia or other neurodegenerative diseases&#xD;
&#xD;
          2. Ages 18-80&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any unstable illness or concomitant medical condition that, in the investigator's&#xD;
             opinion, precludes participation in this study, including disorders that may affect&#xD;
             gait or balance (i.e., stroke, arthritis, etc).&#xD;
&#xD;
          2. Pregnancy or lactation.&#xD;
&#xD;
          3. Concurrent participation in another clinical study.&#xD;
&#xD;
          4. Dementia or other psychiatric illness that prevents the patient from giving informed&#xD;
             consent (Montreal Cognitive Assessment Score score less than or equal to 21).&#xD;
&#xD;
          5. Legal incapacity or limited legal capacity.&#xD;
&#xD;
          6. Tremor derived from any cause other than essential tremor (Parkinson's disease,&#xD;
             drug-induced, anxiety-induced) in the clinical assessment at screening&#xD;
&#xD;
          7. Currently taking lithium or amiodarone or any other drug judged to be contributing to&#xD;
             tremor as judged by the investigator (may be a cause of tremor)&#xD;
&#xD;
          8. No medication is an absolute exclusion from TMS. Medications will be reviewed by the&#xD;
             responsible MD and a decision about inclusion will be made based on the following:&#xD;
&#xD;
               -  The patient's past medical history, drug dose, history of recent medication&#xD;
                  changes or duration of treatment, and combination with other Central Nervous&#xD;
                  System active drugs.&#xD;
&#xD;
               -  The published TMS guidelines review of medications to be considered with TMS&#xD;
&#xD;
          9. History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG, or&#xD;
             family history of treatment resistant epilepsy with the exception of a single seizure&#xD;
             of benign etiology (e.g. febrile seizures) in the judgement of the investigator&#xD;
&#xD;
         10. TMS and MRI-Specific exclusion criteria including:&#xD;
&#xD;
               -  Known metal in the head (such as a surgical aneurysm clip) or a history of prior&#xD;
                  neurosurgical procedures.&#xD;
&#xD;
               -  Ferromagnetic bioimplants activated by any electronic, mechanical or magnetic&#xD;
                  means, such as cochlear implants, pacemakers, medication pumps, vagal&#xD;
                  stimulators, deep brain stimulators, neurostimulators, biostimulators, or&#xD;
                  ventriculo-peritoneal shunts.&#xD;
&#xD;
               -  Subjects who have or might have bullet fragments or other shrapnel (veterans or&#xD;
                  workers exposed to metal in their work environment).&#xD;
&#xD;
               -  Subjects with metallic paint (e.g. color contact lenses, tattoos, metallic&#xD;
                  eyeliner)&#xD;
&#xD;
               -  Subjects expressing significant claustrophobia.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <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>December 2017</verification_date>
  <study_first_submitted>January 6, 2017</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 19, 2017</study_first_posted>
  <last_update_submitted>December 15, 2017</last_update_submitted>
  <last_update_submitted_qc>December 15, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">December 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beth Israel Deaconess Medical Center</investigator_affiliation>
    <investigator_full_name>Ludy Shih</investigator_full_name>
    <investigator_title>Assistant Professor of Neurology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tremor</mesh_term>
    <mesh_term>Essential Tremor</mesh_term>
  </condition_browse>
  <!-- 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/NCT03025529
org study id: 2015P000011
nct id: NCT03025529
lead sponsor: 
has dmc: No
The main purpose of this study is to see if transcranial magnetic stimulation (TMS) can be
      used to help study brain function in healthy people and in those with neurological diseases
      like essential tremor. This portion of the study is being done to establish the optimal
      methods for stimulating the brain to measure its responses.
Essential tremor (ET) is a movement disorder characterized by tremor of both hands, and often
      head and voice, affecting approximately 4.8-6.7 million individuals over the age of 40 in the
      United States alone. Hand tremor can limit basic activities of daily living like feeding,
      drinking, writing and dressing. While medications can be effective for tremor, they are often
      poorly tolerated due to their sedative or neuronal activity depressant properties. Surgical
      options such as deep brain stimulation of the ventral intermedius thalamus (Vim DBS) can be
      highly effective but its invasive nature limits its popularity. Noninvasive brain stimulation
      has demonstrated the ability to reduce tremor but precisely where to target brain stimulation
      to achieve the best results is currently unknown.

      Repetitive transcranial magnetic stimulation (rTMS) enables noninvasive, selective and
      sustained modulation of specific neural networks, and can lead to clinical benefits in
      debilitating neurologic and psychiatric disorders, including medication-resistant depression,
      paresis following stroke or traumatic brain injury, Parkinson's disease, or dementia. There
      is also recent evidence that rTMS of the cerebellum can relieve hand tremor due to essential
      tremor. TMS uses electromagnetic induction to generate controlled currents in targeted brain
      structures that can be identified and defined using MRI-based neuronavigation. TMS is safe if
      appropriate guidelines are adhered to. To date, the impact of rTMS on ET has not been
      sufficiently established, but pilot studies offer promising results.

      The investigators are testing whether MRI-guided neuronavigated cerebellar paired pulse TMS
      demonstrates abnormal physiologic measures in ET subjects compared to controls and whether
      there is reduction of tremor via cerebellar rTMS in patients with ET. The investigators plan
      to collect imaging, functional and neurophysiological assessments before and after the rTMS
      to identify the mechanistic underpinnings of rTMS-induced changes in tremor and
      cerebello-cortical inhibition.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: This is a crossover design with two groups, preceded by a separate single group of healthy controls in a pilot study to assess feasibility of obtaining the cerebellocortical inhibition measure
primary purpose: Device Feasibility
masking: None (Open Label)
masking description: In the single group pilot study, there is no intervention and no masking-- just obtaining an MRI and a cerebellocortical inhibition measure. There were 8 subjects in this phase of the study. There were no subjects enrolled in the crossover design phase of this study.
measure: Tremor Reduction
time frame: One week after intervention
description: tremor rating scale with questions regarding impact of tremor on activities of daily living and an physician-rated assessment of degree of tremor in hands, head, voice, and while drawing and writing
measure: Cerebellocortical Inhibition
time frame: One week after intervention
description: Ratio of conditioned to unconditioned motor evoked potentials
arm group label: Active Cerebellar rTMS
arm group type: Experimental
description: Cerebellar rTMS will be carried out in ET subjects using a MagPro stimulator with a double cone coil at 1Hz (1 pulse every second) for 3 minutes on the left and 3 minutes on the right, at the cerebellar location indicated by resting state functional connectivity MRI analysis. Subjects with ET will undergo 5 consecutive daily sessions of cerebellar rTMS at either the connectivity map generated target or sham rTMS and then crossover to the other target after 2 weeks. Subjects will be blinded to the treatment order assignment. The intensity of the stimulation will be determined as 90% of the resting motor threshold, to be determined at the beginning of the first visit.
arm group label: Sham Cerebellar rTMS
arm group type: Sham Comparator
description: In sham rTMS, the same parameters and procedures as Treatment Procedures 4-8 will be used, except that the coil will be angled 90 degrees from the scalp, resting on one wing of the coil.
arm group label: Healthy control pilot
arm group type: No Intervention
description: This pilot phase is done to assess feasibility of obtaining MRI and cerebellocortical inhibition measures in healthy control subjects.
intervention type: Device
intervention name: Transcranial Magnetic Stimulation
description: Transcranial Magnetic Stimulation or TMS is a noninvasive procedure (meaning it does not enter the body) that is used to stimulate a part of the brain using a magnetic field. This magnetic field can pass through the head safely and painlessly. TMS can be used to change activity in the brain.
arm group label: Active Cerebellar rTMS
other name: TMS
intervention type: Device
intervention name: Sham Transcranial Magnetic Stimulation
description: Sham Transcranial Magnetic Stimulation or sham TMS is like active TMS, a noninvasive procedure (meaning it does not enter the body) that is used to stimulate a part of the brain using a magnetic field. TMS can be used to change activity in the brain but in this intervention, the coil will be angled 90 degrees from the scalp, resting on one wing of the coil, and therefore will not be delivering active TMS.
arm group label: Sham Cerebellar rTMS
other name: Sham TMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Beth Israel Deaconess Medical Center
investigator full name: Ludy Shih
investigator title: Assistant Professor of Neurology
mesh term: Tremor
mesh term: Essential Tremor