<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/NCT03020433</url>
  </required_header>
  <id_info>
    <org_study_id>16-128</org_study_id>
    <secondary_id>16GRNT27720019</secondary_id>
    <nct_id>NCT03020433</nct_id>
  </id_info>
  <brief_title>Novel Brain Stimulation Therapies in Stroke Guided Expressions of Plasticity</brief_title>
  <official_title>Novel Brain Stimulation Therapies in Stroke Guided Expressions of Plasticity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Cleveland Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Cleveland Clinic</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators ultimate goal is to personalize brain stimulation for stroke so outcomes of&#xD;
      the upper limb can be maximized for each individual patient. Several groups including the&#xD;
      investigators have recently theorized that personalizing stimulation so as to selectively&#xD;
      stimulate iM1 in mild, and cPMd in patients with greater severity would help generalize&#xD;
      benefits of stimulation. The investigator premise that variances in expressions of plasticity&#xD;
      can explain how to best stratify patients for robust, personalized stimulation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      AIMS: The ultimate goal is to personalize brain stimulation for stroke so outcomes of the&#xD;
      upper limb can be maximized for each individual patient. Even though stimulation is one of&#xD;
      the most well studied methods to augment plasticity and boost recovery, it is still not&#xD;
      approved for outpatient therapy. Benefits of stimulation are weak and variable especially in&#xD;
      patients who suffer from greater damage and disability. The key limitation of the standard&#xD;
      approach is its generic assumptions about plasticity. The current standard assumes that&#xD;
      ipsilesional primary motor cortex (iM1) can impact recovery for patients in all ranges of&#xD;
      severity, and intact, contralesional cortices always compete with iM1 to inhibit recovery.&#xD;
      But, these long-standing assumptions fail to consider that iM1 or its pathways are damaged in&#xD;
      a majority (58-83%) of patients. As such, the potential of iM1 would be weak and variable,&#xD;
      and patients will have little option but to rely on plasticity of intact, contralesional&#xD;
      cortices that are more likely to survive. Of all surviving cortices, contralesional dorsal&#xD;
      premotor cortex (cPMd) expresses plasticity most consistently. cPMd is activated in movement&#xD;
      of the paretic limb when activating iM1 is less likely. cPMd even reduces its competition&#xD;
      with iM1 and offers its ipsilateral pathways instead to support recovery of the proximal&#xD;
      paretic limb when pathways from iM1 are largely damaged.&#xD;
&#xD;
      Several groups including the investigator have recently theorized that personalizing&#xD;
      stimulation so as to selectively stimulate iM1 in mild, and cPMd in patients with greater&#xD;
      severity would help generalize benefits of stimulation. These theoretical claims, however,&#xD;
      remain untested since several gaps exist. For instance, what is the cut-off level of severity&#xD;
      that stratifies those who respond to stimulation of iM1 from those who respond to stimulation&#xD;
      of cPMd? Even then, are substrates for 'personalized' stimulation same as the substrates that&#xD;
      express plasticity in recovery, i.e. if patients benefit from stimulation of cPMd, do they&#xD;
      express contralesional plasticity in recovery? Here, the investigator premise that variances&#xD;
      in expressions of plasticity can explain how to best stratify patients for robust,&#xD;
      personalized stimulation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 2016</start_date>
  <completion_date type="Actual">December 2019</completion_date>
  <primary_completion_date type="Actual">December 2019</primary_completion_date>
  <phase>Early Phase 1</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>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Aim 1: Change in time (seconds) to perform functional reaching</measure>
    <time_frame>Change in functional reaching from baseline to post rTMS, assessed for approximately 4-6 hours.</time_frame>
    <description>Patients will be seated with test arm resting on a table. Three buttons (labeled 1, 2, 3) will be arranged in a semi-circle at 80% of reaching distance of the paretic limb. A number (1, 2, or 3) will cue patients to reach and push the designated button as fast as possible using shoulder flexion-abduction and elbow extension while their trunk is stabilized. Three blocks of 20 trials will be tested pre- and post-rTMS.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Aim 2:Change in plasticity evoked with rTMS.</measure>
    <time_frame>Change in neurophysiology from baseline to post rTMS assessed for approximately 4-6 hours.</time_frame>
    <description>Expressions of plasticity will be noted for ipsilesional vs. contralesional pathways and inhibition imposed on ipsilesional cortices from contralesional cortices. Subjects will be stratified based on which stimulation location evoked the most plasticity from each of the arms.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">37</enrollment>
  <condition>Stroke</condition>
  <condition>Cerebrovascular Disorders</condition>
  <condition>Nervous System Diseases</condition>
  <condition>Brain Diseases</condition>
  <condition>Cardiovascular Diseases</condition>
  <condition>Vascular Diseases</condition>
  <condition>Central Nervous System Diseases</condition>
  <arm_group>
    <arm_group_label>rTMS Contralesional M1 Inhibition</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>rTMS Contralesional PMC facilitation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>rTMS Ipsilesional PMC facilitation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>rTMS Sham at Ipsilesional M1</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>rTMS Contralesional M1</intervention_name>
    <description>1Hz Contalesional M1 repetitive transcranial magnetic stimulation (1500 pulses, 25 minutes, 90% AMT</description>
    <arm_group_label>rTMS Contralesional M1 Inhibition</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>rTMS Contralesional PMC</intervention_name>
    <description>5Hz Contralesional PMC repetitive transcranial magnetic stimulation (1500 pulses, 10 minutes, 5 trains of 300 pulses each with 1 minute rest in between, 90% AMT)</description>
    <arm_group_label>rTMS Contralesional PMC facilitation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>rTMS Ipsilesional PMC</intervention_name>
    <description>5HZ Ipsilesional PMC repetitive transcranial magnetic stimulation (1500 pulses, 10 minutes, 5 trains of 300 pulses each with 1 minute rest in between, 90% AMT)</description>
    <arm_group_label>rTMS Ipsilesional PMC facilitation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>rTMS sham at Ipsilesional M1</intervention_name>
    <description>1Hz Ipsilesional M1 sham repetitive transcranial magnetic stimulation (1500 pulses, 25 minutes, 50% MSO)</description>
    <arm_group_label>rTMS Sham at Ipsilesional M1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  greater than 21 years old&#xD;
&#xD;
          -  more than 6 months from first, unilateral index stroke&#xD;
&#xD;
          -  unilateral paresis of the upper limb indexed as greater than or equal to 20% slowness&#xD;
             in functional reaching compared to non-paretic limb&#xD;
&#xD;
          -  UEFM less than or equal to 61 out of 66.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  subjects who cannot perform reaching with shoulder&#xD;
&#xD;
          -  severe cognitive deficit (less than or equal to 24 on Mini-Mental State examination.&#xD;
&#xD;
          -  contraindication to TMS or MRI including: seizures, ongoing use of certain neuro- or&#xD;
             psycho-active medications, implants, or pacemaker.&#xD;
&#xD;
          -  currently receiving outpatient therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ela Plow, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Cleveland Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cleveland Clinic Foundation</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>September 6, 2016</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 13, 2017</study_first_posted>
  <last_update_submitted>July 14, 2020</last_update_submitted>
  <last_update_submitted_qc>July 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Cleveland Clinic</investigator_affiliation>
    <investigator_full_name>Ela B. Plow</investigator_full_name>
    <investigator_title>Associate Staff</investigator_title>
  </responsible_party>
  <keyword>Stroke</keyword>
  <keyword>rehab</keyword>
  <keyword>rehabilitation</keyword>
  <keyword>paresis</keyword>
  <keyword>paralysis</keyword>
  <keyword>stroke therapy</keyword>
  <keyword>CVA</keyword>
  <keyword>cerebrovascular accident</keyword>
  <keyword>brain diseases</keyword>
  <keyword>TMS</keyword>
  <keyword>transcranial magnetic stimulation</keyword>
  <keyword>CIMT</keyword>
  <keyword>constraint induced movement therapy</keyword>
  <keyword>MRI</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Nervous System Diseases</mesh_term>
    <mesh_term>Brain Diseases</mesh_term>
    <mesh_term>Central Nervous System Diseases</mesh_term>
    <mesh_term>Cerebrovascular Disorders</mesh_term>
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Vascular Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03020433
org study id: 16-128
secondary id: 16GRNT27720019
nct id: NCT03020433
lead sponsor: 
has dmc: No
The investigators ultimate goal is to personalize brain stimulation for stroke so outcomes of
      the upper limb can be maximized for each individual patient. Several groups including the
      investigators have recently theorized that personalizing stimulation so as to selectively
      stimulate iM1 in mild, and cPMd in patients with greater severity would help generalize
      benefits of stimulation. The investigator premise that variances in expressions of plasticity
      can explain how to best stratify patients for robust, personalized stimulation.
AIMS: The ultimate goal is to personalize brain stimulation for stroke so outcomes of the
      upper limb can be maximized for each individual patient. Even though stimulation is one of
      the most well studied methods to augment plasticity and boost recovery, it is still not
      approved for outpatient therapy. Benefits of stimulation are weak and variable especially in
      patients who suffer from greater damage and disability. The key limitation of the standard
      approach is its generic assumptions about plasticity. The current standard assumes that
      ipsilesional primary motor cortex (iM1) can impact recovery for patients in all ranges of
      severity, and intact, contralesional cortices always compete with iM1 to inhibit recovery.
      But, these long-standing assumptions fail to consider that iM1 or its pathways are damaged in
      a majority (58-83%) of patients. As such, the potential of iM1 would be weak and variable,
      and patients will have little option but to rely on plasticity of intact, contralesional
      cortices that are more likely to survive. Of all surviving cortices, contralesional dorsal
      premotor cortex (cPMd) expresses plasticity most consistently. cPMd is activated in movement
      of the paretic limb when activating iM1 is less likely. cPMd even reduces its competition
      with iM1 and offers its ipsilateral pathways instead to support recovery of the proximal
      paretic limb when pathways from iM1 are largely damaged.

      Several groups including the investigator have recently theorized that personalizing
      stimulation so as to selectively stimulate iM1 in mild, and cPMd in patients with greater
      severity would help generalize benefits of stimulation. These theoretical claims, however,
      remain untested since several gaps exist. For instance, what is the cut-off level of severity
      that stratifies those who respond to stimulation of iM1 from those who respond to stimulation
      of cPMd? Even then, are substrates for 'personalized' stimulation same as the substrates that
      express plasticity in recovery, i.e. if patients benefit from stimulation of cPMd, do they
      express contralesional plasticity in recovery? Here, the investigator premise that variances
      in expressions of plasticity can explain how to best stratify patients for robust,
      personalized stimulation.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Supportive Care
masking: Single (Participant)
measure: Aim 1: Change in time (seconds) to perform functional reaching
time frame: Change in functional reaching from baseline to post rTMS, assessed for approximately 4-6 hours.
description: Patients will be seated with test arm resting on a table. Three buttons (labeled 1, 2, 3) will be arranged in a semi-circle at 80% of reaching distance of the paretic limb. A number (1, 2, or 3) will cue patients to reach and push the designated button as fast as possible using shoulder flexion-abduction and elbow extension while their trunk is stabilized. Three blocks of 20 trials will be tested pre- and post-rTMS.
measure: Aim 2:Change in plasticity evoked with rTMS.
time frame: Change in neurophysiology from baseline to post rTMS assessed for approximately 4-6 hours.
description: Expressions of plasticity will be noted for ipsilesional vs. contralesional pathways and inhibition imposed on ipsilesional cortices from contralesional cortices. Subjects will be stratified based on which stimulation location evoked the most plasticity from each of the arms.
arm group label: rTMS Contralesional M1 Inhibition
arm group type: Active Comparator
arm group label: rTMS Contralesional PMC facilitation
arm group type: Active Comparator
arm group label: rTMS Ipsilesional PMC facilitation
arm group type: Active Comparator
arm group label: rTMS Sham at Ipsilesional M1
arm group type: Sham Comparator
intervention type: Device
intervention name: rTMS Contralesional M1
description: 1Hz Contalesional M1 repetitive transcranial magnetic stimulation (1500 pulses, 25 minutes, 90% AMT
arm group label: rTMS Contralesional M1 Inhibition
intervention type: Device
intervention name: rTMS Contralesional PMC
description: 5Hz Contralesional PMC repetitive transcranial magnetic stimulation (1500 pulses, 10 minutes, 5 trains of 300 pulses each with 1 minute rest in between, 90% AMT)
arm group label: rTMS Contralesional PMC facilitation
intervention type: Device
intervention name: rTMS Ipsilesional PMC
description: 5HZ Ipsilesional PMC repetitive transcranial magnetic stimulation (1500 pulses, 10 minutes, 5 trains of 300 pulses each with 1 minute rest in between, 90% AMT)
arm group label: rTMS Ipsilesional PMC facilitation
intervention type: Device
intervention name: rTMS sham at Ipsilesional M1
description: 1Hz Ipsilesional M1 sham repetitive transcranial magnetic stimulation (1500 pulses, 25 minutes, 50% MSO)
arm group label: rTMS Sham at Ipsilesional M1
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Ela Plow, PhD
role: Principal Investigator
affiliation: The Cleveland Clinic
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Cleveland Clinic
investigator full name: Ela B. Plow
investigator title: Associate Staff
mesh term: Stroke
mesh term: Nervous System Diseases
mesh term: Brain Diseases
mesh term: Central Nervous System Diseases
mesh term: Cerebrovascular Disorders
mesh term: Cardiovascular Diseases
mesh term: Vascular Diseases
sharing ipd: No