<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/NCT03025269</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00001202</org_study_id>
    <nct_id>NCT03025269</nct_id>
  </id_info>
  <brief_title>Ocrelizumab Effects on Physiological and Cognitive Changes in Multiple Sclerosis</brief_title>
  <official_title>Effect of Ocrelizumab on Gray Matter Pathology, Leptomeningeal Inflammation and Cognitive Dysfunction in Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University at Buffalo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University at Buffalo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase IV, prospective, open-label, single-center, observational, longitudinal,&#xD;
      single blinded study. The investigators will examine the effects of Ocrelizumab on cognitive,&#xD;
      patient reported outcomes (PROs), quality of life (QoL), multiple sclerosis functional&#xD;
      composite (MSFC), working status and magnetic resonance imaging (MRI) outcomes across 12 and&#xD;
      24 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Grey matter (GM) atrophy develops early in the multiple sclerosis (MS) disease process. Over&#xD;
      2 years, clinically isolated syndrome (CIS) patients developed significant thalamic and&#xD;
      cortical volume loss. In our preliminary study, including 50 MS patients, the investigators&#xD;
      found that the presence of leptomeningeal (LM) contrast enhancement (CE) was associated with&#xD;
      progression of cortical atrophy over 5 years, as measured by the loss of cortical volume, in&#xD;
      patients with MS. About 40% of relapsing-remitting MS (RRMS) patients presented with LM CE.&#xD;
      MS patients with LM CE showed significantly greater percentage decreases cortical (-3.4% vs.&#xD;
      -1.8%, p=0.007) volumes, compared to those without. RRMS patients with LM CE showed&#xD;
      significantly greater percentage decrease in cortical (-3.8% vs. -1.9%, p=0.006) volume over&#xD;
      the follow-up, compared to those without. No differences in deep GM volume changes were found&#xD;
      in relapsing-remitting (RR) and secondary progressive (SP) MS patients with and without LM&#xD;
      CE. Three LM CE positive and one LM CE negative RRMS patients developed secondary progressive&#xD;
      MS (SPMS) course over the follow-up. More MS subjects with LM CE had disability progression&#xD;
      (7, 28%) compared to those without (4, 16%), but this was not significantly different&#xD;
      (p=0.306). The median EDSS in MS patient with LM CE increased to 4.0, while decreased to 2.5&#xD;
      in those without. No differences in total number of relapses, annual relapse rate, nor being&#xD;
      relapse free were detected in MS patients with and without LM CE over the follow-up. However,&#xD;
      in RRMS patients with LM CE, the investigators found that there was a trend for greater&#xD;
      increase in absolute change of EDSS (0.9 vs. -0.03, p=0.05).&#xD;
&#xD;
      The proposed study will extend these preliminary findings in a cohort of MS patients, who&#xD;
      will be treated with Ocrelizumab and who will be assessed at 12 and 24 months using same MRI&#xD;
      hardware and software. The longitudinal serial MRI assessment study design will allow us to&#xD;
      examine temporal relationship of LM CE, development of GM pathology, cognitive dysfunction&#xD;
      and Ocrelizumab. Based on our preliminary results, the investigators expect that&#xD;
      approximately 12 (40%) of MS patients will present with LM CE at baseline in the proposed&#xD;
      study.&#xD;
&#xD;
      Substantial evidence shows that Epstein-Barr virus (EBV) infection plays a major role in the&#xD;
      risk of developing MS. Mononucleosis and seropositivity of anti-Epstein-Barr nuclear antigen&#xD;
      (EBNA) Immunoglobulin G (IgG) along with Vit D deficiency and smoking are risk factors for&#xD;
      MS. Serial studies reveal that the risk of developing MS is extremely low among individuals&#xD;
      not infected with EBV but increases sharply in the same individuals following EBV infection.&#xD;
      EBV-infected B cells were identified in MS brain lesions. Therefore the elimination of the&#xD;
      virus from the persistently infected B-cells could potentially inhibit/delay disease&#xD;
      progression. Our data show correlation of anti-EBV levels with atrophy (more degeneration)&#xD;
      hence an effect on disease chronicity/progression. Besides high Vit D administration studies&#xD;
      that showed an effect on decreasing the EBV antibody levels, no other DMT's were able to show&#xD;
      a beneficial effect on EBV antibody level, and some treatments increased EBV levels.&#xD;
&#xD;
      EBV viremia occurs in the hematopoietic stem transplantation setting and has been treated&#xD;
      successfully with rituximab, an antibody that targets B-lymphocyte antigen (CD20) on B cells&#xD;
      in a manner analogous to Ocrelizumab. It has been reported that 92% of patients with EBV&#xD;
      viremia responded upon dosing with rituximab and the EBV copies per 100,000 peripheral blood&#xD;
      mononuclear cell (PBMC) decreased from 2578 to 71 at Day 15 and 0 by Day 21.&#xD;
&#xD;
      Therefore, our hypothesis is that Ocrelizumab treatment will reduce both B cells and EBV&#xD;
      exposure in treated patients leading to benefit on LM inflammation and to less GM atrophy&#xD;
      development.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 15, 2017</start_date>
  <completion_date type="Actual">January 8, 2022</completion_date>
  <primary_completion_date type="Actual">January 8, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Absolute cortical atrophy 12</measure>
    <time_frame>12 months</time_frame>
    <description>Absolute change in cortical atrophy between baseline and 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent change cortical atrophy 12</measure>
    <time_frame>12 months</time_frame>
    <description>Percent change in cortical atrophy between baseline and 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Absolute cortical atrophy 24</measure>
    <time_frame>24 months</time_frame>
    <description>Absolute change in cortical atrophy between baseline and 24 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent cortical atrophy 24</measure>
    <time_frame>24 months</time_frame>
    <description>Percent change in cortical atrophy between baseline and 24 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Absolute thalamic atrophy 12</measure>
    <time_frame>12 months</time_frame>
    <description>Absolute change in thalamic atrophy between baseline and 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent thalamic atrophy 12</measure>
    <time_frame>12 months</time_frame>
    <description>Percent change in thalamic atrophy between baseline and 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Absolute thalamic atrophy 24</measure>
    <time_frame>24 months</time_frame>
    <description>Absolute change in thalamic atrophy between baseline and 24 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent thalamic atrophy 24</measure>
    <time_frame>24 months</time_frame>
    <description>Percent change in thalamic atrophy between baseline and 24 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inflammation foci 12</measure>
    <time_frame>12 months</time_frame>
    <description>Number of leptomeningeal inflammation foci at 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inflammation foci 24</measure>
    <time_frame>24 months</time_frame>
    <description>Number of leptomeningeal inflammation foci at 24 months</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>SDMT score 12</measure>
    <time_frame>12 months</time_frame>
    <description>Raw score differences on Symbol Digit Modalities Test score between baseline and 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SDMT 24</measure>
    <time_frame>24 months</time_frame>
    <description>Raw score differences on Symbol Digit Modalities Test score between baseline and 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Memory 12</measure>
    <time_frame>12 months</time_frame>
    <description>Differences in Brief Visuospatial Memory Test Revised between baseline and 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Memory 24</measure>
    <time_frame>24 months</time_frame>
    <description>Differences in Brief Visuospatial Memory Test Revised between baseline and 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Verbal learning 12</measure>
    <time_frame>12 months</time_frame>
    <description>Differences in California Verbal Learning Test Revised between baseline and 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Verbal learning 24</measure>
    <time_frame>24 months</time_frame>
    <description>Differences in California Verbal Learning Test Revised between baseline and 24 months</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">30</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Relapsing MS patients treated with Ocrelizumab</arm_group_label>
    <description>30 patients diagnosed with relapsing forms of multiple sclerosis and newly beginning treatment with Ocrelizumab according to neurologists' orders</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ocrelizumab</intervention_name>
    <description>This is not a drug intervention study, we are doing an observational study with those who have been prescribed Ocrelizumab by their neurologists during clinical routine appointments</description>
    <arm_group_label>Relapsing MS patients treated with Ocrelizumab</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients diagnosed with relapsing multiple sclerosis who are being treated at the Jacobs&#xD;
        Neurological Institute (JNI) in Buffalo, NY&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient diagnosed with MS according to McDonald criteria&#xD;
&#xD;
          -  Age 18-60&#xD;
&#xD;
          -  Relapsing disease course&#xD;
&#xD;
          -  Expanded Disability Status Scale (EDSS) ≤5.5&#xD;
&#xD;
          -  Disease duration &lt;20 years&#xD;
&#xD;
          -  Treatment naive to Ocrelizumab&#xD;
&#xD;
          -  Willing and able to comply with the study procedures for the duration of the trial&#xD;
&#xD;
          -  Given written informed consent and signed HIPAA Authorization prior to the study&#xD;
&#xD;
          -  Normal kidney functioning (creatinine clearance &gt;59)&#xD;
&#xD;
          -  None of the exclusion criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  PI guidelines for contraindications of Ocrelizumab (available after FDA approval)&#xD;
&#xD;
          -  Significant cognitive impairment (in the opinion of the investigator) or other&#xD;
             significant neurological or medical condition that would compromise adherence and&#xD;
             completion of the trial, including major depression and developmental disorders&#xD;
             affecting cognition&#xD;
&#xD;
          -  Have received treatment within 30 days prior to enrollment with steroids or any other&#xD;
             concomitant immunomodulatory therapies&#xD;
&#xD;
          -  Have received treatment with Natalizumab within 8 weeks prior to enrollment; this is&#xD;
             needed to increase confidence that there are no signs of progressive multifocal&#xD;
             leukoencephalopathy (PML) on baseline MRI&#xD;
&#xD;
          -  Less than 6 months from the use of immunosuppressant agents (e.g., including but not&#xD;
             limited to mitoxantrone, cyclophosphamide, azathioprine, methotrexate, mycophenolate&#xD;
             mofetil)&#xD;
&#xD;
          -  Have received an investigational drug or experimental procedure within the past 30&#xD;
             days&#xD;
&#xD;
          -  Women who are pregnant, lactating, or of childbearing age who do not consent to&#xD;
             approved contraceptive use during the study&#xD;
&#xD;
          -  Any other factor that, in the opinion of the investigator, would make the subject&#xD;
             unsuitable for participation in this study&#xD;
&#xD;
          -  Hypersensitivity to trial medications&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Jacobs Institute</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>January 16, 2017</study_first_submitted>
  <study_first_submitted_qc>January 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 19, 2017</study_first_posted>
  <last_update_submitted>March 9, 2022</last_update_submitted>
  <last_update_submitted_qc>March 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University at Buffalo</investigator_affiliation>
    <investigator_full_name>Robert Zivadinov, MD, PhD</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ocrelizumab</mesh_term>
  </intervention_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/NCT03025269
org study id: STUDY00001202
nct id: NCT03025269
lead sponsor: 
has dmc: No
This is a Phase IV, prospective, open-label, single-center, observational, longitudinal,
      single blinded study. The investigators will examine the effects of Ocrelizumab on cognitive,
      patient reported outcomes (PROs), quality of life (QoL), multiple sclerosis functional
      composite (MSFC), working status and magnetic resonance imaging (MRI) outcomes across 12 and
      24 months.
Grey matter (GM) atrophy develops early in the multiple sclerosis (MS) disease process. Over
      2 years, clinically isolated syndrome (CIS) patients developed significant thalamic and
      cortical volume loss. In our preliminary study, including 50 MS patients, the investigators
      found that the presence of leptomeningeal (LM) contrast enhancement (CE) was associated with
      progression of cortical atrophy over 5 years, as measured by the loss of cortical volume, in
      patients with MS. About 40% of relapsing-remitting MS (RRMS) patients presented with LM CE.
      MS patients with LM CE showed significantly greater percentage decreases cortical (-3.4% vs.
      -1.8%, p=0.007) volumes, compared to those without. RRMS patients with LM CE showed
      significantly greater percentage decrease in cortical (-3.8% vs. -1.9%, p=0.006) volume over
      the follow-up, compared to those without. No differences in deep GM volume changes were found
      in relapsing-remitting (RR) and secondary progressive (SP) MS patients with and without LM
      CE. Three LM CE positive and one LM CE negative RRMS patients developed secondary progressive
      MS (SPMS) course over the follow-up. More MS subjects with LM CE had disability progression
      (7, 28%) compared to those without (4, 16%), but this was not significantly different
      (p=0.306). The median EDSS in MS patient with LM CE increased to 4.0, while decreased to 2.5
      in those without. No differences in total number of relapses, annual relapse rate, nor being
      relapse free were detected in MS patients with and without LM CE over the follow-up. However,
      in RRMS patients with LM CE, the investigators found that there was a trend for greater
      increase in absolute change of EDSS (0.9 vs. -0.03, p=0.05).

      The proposed study will extend these preliminary findings in a cohort of MS patients, who
      will be treated with Ocrelizumab and who will be assessed at 12 and 24 months using same MRI
      hardware and software. The longitudinal serial MRI assessment study design will allow us to
      examine temporal relationship of LM CE, development of GM pathology, cognitive dysfunction
      and Ocrelizumab. Based on our preliminary results, the investigators expect that
      approximately 12 (40%) of MS patients will present with LM CE at baseline in the proposed
      study.

      Substantial evidence shows that Epstein-Barr virus (EBV) infection plays a major role in the
      risk of developing MS. Mononucleosis and seropositivity of anti-Epstein-Barr nuclear antigen
      (EBNA) Immunoglobulin G (IgG) along with Vit D deficiency and smoking are risk factors for
      MS. Serial studies reveal that the risk of developing MS is extremely low among individuals
      not infected with EBV but increases sharply in the same individuals following EBV infection.
      EBV-infected B cells were identified in MS brain lesions. Therefore the elimination of the
      virus from the persistently infected B-cells could potentially inhibit/delay disease
      progression. Our data show correlation of anti-EBV levels with atrophy (more degeneration)
      hence an effect on disease chronicity/progression. Besides high Vit D administration studies
      that showed an effect on decreasing the EBV antibody levels, no other DMT's were able to show
      a beneficial effect on EBV antibody level, and some treatments increased EBV levels.

      EBV viremia occurs in the hematopoietic stem transplantation setting and has been treated
      successfully with rituximab, an antibody that targets B-lymphocyte antigen (CD20) on B cells
      in a manner analogous to Ocrelizumab. It has been reported that 92% of patients with EBV
      viremia responded upon dosing with rituximab and the EBV copies per 100,000 peripheral blood
      mononuclear cell (PBMC) decreased from 2578 to 71 at Day 15 and 0 by Day 21.

      Therefore, our hypothesis is that Ocrelizumab treatment will reduce both B cells and EBV
      exposure in treated patients leading to benefit on LM inflammation and to less GM atrophy
      development.
observational model: Case-Only
time perspective: Prospective
measure: Absolute cortical atrophy 12
time frame: 12 months
description: Absolute change in cortical atrophy between baseline and 12 months
measure: Percent change cortical atrophy 12
time frame: 12 months
description: Percent change in cortical atrophy between baseline and 12 months
measure: Absolute cortical atrophy 24
time frame: 24 months
description: Absolute change in cortical atrophy between baseline and 24 months
measure: Percent cortical atrophy 24
time frame: 24 months
description: Percent change in cortical atrophy between baseline and 24 months
measure: Absolute thalamic atrophy 12
time frame: 12 months
description: Absolute change in thalamic atrophy between baseline and 12 months
measure: Percent thalamic atrophy 12
time frame: 12 months
description: Percent change in thalamic atrophy between baseline and 12 months
measure: Absolute thalamic atrophy 24
time frame: 24 months
description: Absolute change in thalamic atrophy between baseline and 24 months
measure: Percent thalamic atrophy 24
time frame: 24 months
description: Percent change in thalamic atrophy between baseline and 24 months
measure: Inflammation foci 12
time frame: 12 months
description: Number of leptomeningeal inflammation foci at 12 months
measure: Inflammation foci 24
time frame: 24 months
description: Number of leptomeningeal inflammation foci at 24 months
measure: SDMT score 12
time frame: 12 months
description: Raw score differences on Symbol Digit Modalities Test score between baseline and 12 months
measure: SDMT 24
time frame: 24 months
description: Raw score differences on Symbol Digit Modalities Test score between baseline and 24 months
measure: Memory 12
time frame: 12 months
description: Differences in Brief Visuospatial Memory Test Revised between baseline and 12 months
measure: Memory 24
time frame: 24 months
description: Differences in Brief Visuospatial Memory Test Revised between baseline and 24 months
measure: Verbal learning 12
time frame: 12 months
description: Differences in California Verbal Learning Test Revised between baseline and 12 months
measure: Verbal learning 24
time frame: 24 months
description: Differences in California Verbal Learning Test Revised between baseline and 24 months
arm group label: Relapsing MS patients treated with Ocrelizumab
description: 30 patients diagnosed with relapsing forms of multiple sclerosis and newly beginning treatment with Ocrelizumab according to neurologists' orders
intervention type: Drug
intervention name: Ocrelizumab
description: This is not a drug intervention study, we are doing an observational study with those who have been prescribed Ocrelizumab by their neurologists during clinical routine appointments
arm group label: Relapsing MS patients treated with Ocrelizumab
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University at Buffalo
investigator full name: Robert Zivadinov, MD, PhD
investigator title: MD, PhD
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Ocrelizumab
sharing ipd: No