<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/NCT03243721</url>
  </required_header>
  <id_info>
    <org_study_id>CCF 17-766</org_study_id>
    <nct_id>NCT03243721</nct_id>
  </id_info>
  <brief_title>Gilenya's Impact on Cognitive Function and Thalamic Volumes</brief_title>
  <official_title>Impact of Gilenya on Cognitive Function and Thalamic Volume Measured by 7 Tesla MRI in Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Cleveland Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The Cleveland Clinic</source>
  <oversight_info>
    <has_dmc>No</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>
      This evaluation will be a one-year feasibility study to characterize the neuroprotective&#xD;
      benefits of Gilenya and its effects on cognition and grey matter volumes. The study will&#xD;
      enroll 15 patients with relapsing-remitting multiple sclerosis being treated with Gilenya and&#xD;
      5 healthy controls. Each participant will undergo a battery of neurometric testing at&#xD;
      baseline, six months, and one year. In addition, patients will undergo high-field 7T MRI at&#xD;
      the same time points.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cognitive impairment is a well-recognized manifestation of multiple sclerosis (MS) with&#xD;
      prevalence estimates ranging from 43 to 70%. It is also known to occur as early as the first&#xD;
      demyelinating event and is a major factor contributing to quality of life in MS. Treatment&#xD;
      strategies for cognitive impairment in MS are limited. Several agents have been tested as&#xD;
      therapeutics for MS-related cognitive dysfunction and have showed no major benefit. Cognitive&#xD;
      rehabilitation has shown some promise, but the data are limited and many studies have&#xD;
      suffered from methodological shortcomings. Given the lack of well-established treatment&#xD;
      options and the substantial impact of cognitive impairment, protection of cognitive function&#xD;
      from the earliest stages of the disease is of great importance.&#xD;
&#xD;
      Cognitive outcomes received relatively little attention in the pivotal studies of MS disease&#xD;
      modifying therapies (DMT), but some data suggest that DMT may have a positive impact on&#xD;
      cognition. Gilenya is of special interest because it was found to have a significant&#xD;
      protective effect on whole brain atrophy when compared against placebo and intramuscular&#xD;
      interferon β-1a in two phase III studies, showing a 31-35% reduction in percentage brain&#xD;
      volume change. Gilenya's effect on whole brain atrophy leads to the natural hypothesis that&#xD;
      it may have a beneficial effect on cognitive function in MS. Also of particular interest is&#xD;
      the extent to which protection of the thalamus and cortex contributes to Gilenya's effect on&#xD;
      whole brain atrophy and possible effects on cognition.&#xD;
&#xD;
      The study will enroll 15 subjects from the Cleveland Clinic Mellen Center patient population.&#xD;
      Participants must have been on Gilenya for at least 6 months at the time of study entry. The&#xD;
      study will involve three assessments: at baseline, six months, and one year. At each time&#xD;
      point, participants will undergo 7T MRI of the brain with and without contrast. Participants&#xD;
      will also undergo a battery of neurometric testing at each time point. The tests will include&#xD;
      the Brief Visuospatial Memory Test - Revised (visuospatial skills), the iPadTM Processing&#xD;
      Speed Test (processing speed), the Selective Reminding Test (verbal learning and memory), and&#xD;
      the Delis-Kaplan Executive Function System Sorting Test (problem-solving skills; can only be&#xD;
      administered at baseline and one year due to version limitations).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 20, 2017</start_date>
  <completion_date type="Actual">November 12, 2019</completion_date>
  <primary_completion_date type="Actual">November 12, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>There will be two groups running in parallel. One will be MS patients (15) and the other will be control patients (5). Both groups will receive the same interventions.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>There is no masking in this study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Thalamic volume to cognitive performance</measure>
    <time_frame>One year.</time_frame>
    <description>Spearman's correlation coefficient of change in thalamic volume and change in cognitive function from baseline to one year in RRMS patients treated with Gilenya.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Thalamic volume to other MRI metrics</measure>
    <time_frame>Six months and one year.</time_frame>
    <description>Ratio of change in thalamic volume from baseline to six months and from baseline to one year to 1) change in brain volume (from baseline to six months and from baseline to one year); 2) change in T2 lesion volume (from baseline to six months and from baseline to one year); and 3) change in cortical thickness (from baseline to six months and from baseline to one year).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thalamic nuclei to cognitive performance</measure>
    <time_frame>Six months and one year.</time_frame>
    <description>Spearman correlation coefficient for change in the volume of each thalamic nuclei (from baseline to six months and from baseline to one year) and change in cognitive testing scores (from baseline to six months and from baseline to one year).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thalamic myelin density to cognitive performance</measure>
    <time_frame>Six months and one year.</time_frame>
    <description>Spearman correlation coefficient of change in thalamic myelin density (from baseline to six months and from baseline to one year) to change in cognitive test performance (from baseline to six months and from baseline to one year).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thalamic axon density to cognitive performance</measure>
    <time_frame>Six months and one year.</time_frame>
    <description>Spearman correlation coefficient of change in thalamic axon density (from baseline to six months and from baseline to one year) to change in cognitive test performance (from baseline to six months and from baseline to one year).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in MRI metrics in Gilenya treated patients vs. controls</measure>
    <time_frame>Six months and one year.</time_frame>
    <description>Ratio of change in each of the following between Gilenya treated MS patients and healthy controls: 1.) Thalamic volume change (from baseline to six months and from baseline to one year); 2) Cortical thickness change (from baseline to six months and from baseline to one year); 3) thalamic axon density change (from baseline to six months and from baseline to one year); 4) thalamic myelin density (from baseline to six months and from baseline to one year).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in cognitive performance in Gilenya treated patients vs controls</measure>
    <time_frame>Six months and one year.</time_frame>
    <description>Ratio of change in cognitive test performance (from baseline to six months and from baseline to one year) between Gilenya treated patients and controls.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thalamic volume to cognitive performance</measure>
    <time_frame>Six months.</time_frame>
    <description>Spearman's correlation coefficient of change in thalamic volume and change in cognitive function from baseline to six months in RRMS patients treated with Gilenya.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Gilenya treated MS patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Multiple sclerosis patients treated with Gilenya for at least six months. This group will receive diagnostic tests: 7T MRI and Neurocognitive testing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects without multiple sclerosis or other diseases of the central nervous system. This group will receive diagnostic tests: 7T MRI and Neurocognitive testing.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>7T MRI</intervention_name>
    <description>A high field MRI that will take approximately one hour.</description>
    <arm_group_label>Gilenya treated MS patients</arm_group_label>
    <arm_group_label>Healthy controls</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Neurocognitive testing</intervention_name>
    <description>A series of tests to assess memory, verbal skills, and visuospatial skills.</description>
    <arm_group_label>Gilenya treated MS patients</arm_group_label>
    <arm_group_label>Healthy controls</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria (MS Patients):&#xD;
&#xD;
          1. RRMS phenotype&#xD;
&#xD;
          2. Treated with Gilenya for ≥6 months at the time of the baseline visit.&#xD;
&#xD;
          3. Age 18-50 inclusive.&#xD;
&#xD;
          4. EDSS 0-4.0&#xD;
&#xD;
          5. Disease duration of 5-15 years.&#xD;
&#xD;
          6. At least 12 years of education (high school diploma or general equivalency diploma).&#xD;
&#xD;
          7. Physically capable of completing neurometric testing and MRI studies.&#xD;
&#xD;
        Inclusion Criteria (Healthy Controls):&#xD;
&#xD;
          1. Age 18-50 inclusive.&#xD;
&#xD;
          2. At least 12 years of education (high school diploma or general equivalency diploma)&#xD;
&#xD;
          3. Physically capable of completing neurometric testing and MRI studies.&#xD;
&#xD;
        Exclusion Criteria (MS Patients):&#xD;
&#xD;
          1. Contraindication to MRI (e.g. metal implants)&#xD;
&#xD;
          2. Current use of immunomodulatory or immunosuppressant medications other than Gilenya.&#xD;
&#xD;
          3. Disease of the central nervous system other than MS (e.g. Alzheimer disease, stroke,&#xD;
             epilepsy).&#xD;
&#xD;
          4. Use of anti-psychotic or psychostimulant medications. Patients started on modafinil or&#xD;
             armodafinil more than six months prior to enrollment will not be excluded.&#xD;
&#xD;
          5. Ongoing major depressive disorder that, in the opinion of the investigator, may affect&#xD;
             cognitive functioning.&#xD;
&#xD;
          6. MS relapse within 90 days of study entry.&#xD;
&#xD;
          7. Treatment with corticosteroids within 90 days of study entry.&#xD;
&#xD;
          8. Current illicit substance use.&#xD;
&#xD;
          9. History of alcohol or drug abuse.&#xD;
&#xD;
        Exclusion Criteria (Healthy Controls):&#xD;
&#xD;
          1. Contraindication to MRI (e.g. metal implants, claustrophobia).&#xD;
&#xD;
          2. Disease of the central nervous system (e.g. MS, Alzheimer disease, stroke, epilepsy).&#xD;
&#xD;
          3. Use of anti-psychotic or psychostimulant medications. Patients started on modafinil or&#xD;
             armodafinil more than six months ago will not be excluded.&#xD;
&#xD;
          4. Ongoing major depressive disorder that, in the opinion of the investigator, may affect&#xD;
             cognitive functioning.&#xD;
&#xD;
          5. Current illicit substance use.&#xD;
&#xD;
          6. History of alcohol or drug abuse.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Devon S Conway, MD</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>September 2021</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>September 2, 2021</last_update_submitted>
  <last_update_submitted_qc>September 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Cleveland Clinic</investigator_affiliation>
    <investigator_full_name>Devon Conway MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>multiple sclerosis</keyword>
  <keyword>thalamus</keyword>
  <keyword>high field MRI</keyword>
  <keyword>cognition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>The data will be analyzed in aggregate. There is no plan to share individual participant data with other researchers.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03243721
org study id: CCF 17-766
nct id: NCT03243721
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This evaluation will be a one-year feasibility study to characterize the neuroprotective
      benefits of Gilenya and its effects on cognition and grey matter volumes. The study will
      enroll 15 patients with relapsing-remitting multiple sclerosis being treated with Gilenya and
      5 healthy controls. Each participant will undergo a battery of neurometric testing at
      baseline, six months, and one year. In addition, patients will undergo high-field 7T MRI at
      the same time points.
Cognitive impairment is a well-recognized manifestation of multiple sclerosis (MS) with
      prevalence estimates ranging from 43 to 70%. It is also known to occur as early as the first
      demyelinating event and is a major factor contributing to quality of life in MS. Treatment
      strategies for cognitive impairment in MS are limited. Several agents have been tested as
      therapeutics for MS-related cognitive dysfunction and have showed no major benefit. Cognitive
      rehabilitation has shown some promise, but the data are limited and many studies have
      suffered from methodological shortcomings. Given the lack of well-established treatment
      options and the substantial impact of cognitive impairment, protection of cognitive function
      from the earliest stages of the disease is of great importance.

      Cognitive outcomes received relatively little attention in the pivotal studies of MS disease
      modifying therapies (DMT), but some data suggest that DMT may have a positive impact on
      cognition. Gilenya is of special interest because it was found to have a significant
      protective effect on whole brain atrophy when compared against placebo and intramuscular
      interferon β-1a in two phase III studies, showing a 31-35% reduction in percentage brain
      volume change. Gilenya's effect on whole brain atrophy leads to the natural hypothesis that
      it may have a beneficial effect on cognitive function in MS. Also of particular interest is
      the extent to which protection of the thalamus and cortex contributes to Gilenya's effect on
      whole brain atrophy and possible effects on cognition.

      The study will enroll 15 subjects from the Cleveland Clinic Mellen Center patient population.
      Participants must have been on Gilenya for at least 6 months at the time of study entry. The
      study will involve three assessments: at baseline, six months, and one year. At each time
      point, participants will undergo 7T MRI of the brain with and without contrast. Participants
      will also undergo a battery of neurometric testing at each time point. The tests will include
      the Brief Visuospatial Memory Test - Revised (visuospatial skills), the iPadTM Processing
      Speed Test (processing speed), the Selective Reminding Test (verbal learning and memory), and
      the Delis-Kaplan Executive Function System Sorting Test (problem-solving skills; can only be
      administered at baseline and one year due to version limitations).
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: There will be two groups running in parallel. One will be MS patients (15) and the other will be control patients (5). Both groups will receive the same interventions.
primary purpose: Other
masking: None (Open Label)
masking description: There is no masking in this study.
measure: Thalamic volume to cognitive performance
time frame: One year.
description: Spearman's correlation coefficient of change in thalamic volume and change in cognitive function from baseline to one year in RRMS patients treated with Gilenya.
measure: Thalamic volume to other MRI metrics
time frame: Six months and one year.
description: Ratio of change in thalamic volume from baseline to six months and from baseline to one year to 1) change in brain volume (from baseline to six months and from baseline to one year); 2) change in T2 lesion volume (from baseline to six months and from baseline to one year); and 3) change in cortical thickness (from baseline to six months and from baseline to one year).
measure: Thalamic nuclei to cognitive performance
time frame: Six months and one year.
description: Spearman correlation coefficient for change in the volume of each thalamic nuclei (from baseline to six months and from baseline to one year) and change in cognitive testing scores (from baseline to six months and from baseline to one year).
measure: Thalamic myelin density to cognitive performance
time frame: Six months and one year.
description: Spearman correlation coefficient of change in thalamic myelin density (from baseline to six months and from baseline to one year) to change in cognitive test performance (from baseline to six months and from baseline to one year).
measure: Thalamic axon density to cognitive performance
time frame: Six months and one year.
description: Spearman correlation coefficient of change in thalamic axon density (from baseline to six months and from baseline to one year) to change in cognitive test performance (from baseline to six months and from baseline to one year).
measure: Changes in MRI metrics in Gilenya treated patients vs. controls
time frame: Six months and one year.
description: Ratio of change in each of the following between Gilenya treated MS patients and healthy controls: 1.) Thalamic volume change (from baseline to six months and from baseline to one year); 2) Cortical thickness change (from baseline to six months and from baseline to one year); 3) thalamic axon density change (from baseline to six months and from baseline to one year); 4) thalamic myelin density (from baseline to six months and from baseline to one year).
measure: Changes in cognitive performance in Gilenya treated patients vs controls
time frame: Six months and one year.
description: Ratio of change in cognitive test performance (from baseline to six months and from baseline to one year) between Gilenya treated patients and controls.
measure: Thalamic volume to cognitive performance
time frame: Six months.
description: Spearman's correlation coefficient of change in thalamic volume and change in cognitive function from baseline to six months in RRMS patients treated with Gilenya.
arm group label: Gilenya treated MS patients
arm group type: Experimental
description: Multiple sclerosis patients treated with Gilenya for at least six months. This group will receive diagnostic tests: 7T MRI and Neurocognitive testing.
arm group label: Healthy controls
arm group type: Experimental
description: Subjects without multiple sclerosis or other diseases of the central nervous system. This group will receive diagnostic tests: 7T MRI and Neurocognitive testing.
intervention type: Diagnostic Test
intervention name: 7T MRI
description: A high field MRI that will take approximately one hour.
arm group label: Gilenya treated MS patients
arm group label: Healthy controls
intervention type: Diagnostic Test
intervention name: Neurocognitive testing
description: A series of tests to assess memory, verbal skills, and visuospatial skills.
arm group label: Gilenya treated MS patients
arm group label: Healthy controls
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Devon S Conway, MD
role: Principal Investigator
affiliation: The Cleveland Clinic
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Cleveland Clinic
investigator full name: Devon Conway MD
investigator title: Principal Investigator
mesh term: Multiple Sclerosis
mesh term: Sclerosis
sharing ipd: No
ipd description: The data will be analyzed in aggregate. There is no plan to share individual participant data with other researchers.