<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/NCT03835728</url>
  </required_header>
  <id_info>
    <org_study_id>STU-2018-0185</org_study_id>
    <nct_id>NCT03835728</nct_id>
  </id_info>
  <brief_title>Efficacy of Ocrelizumab in Autoimmune Encephalitis</brief_title>
  <official_title>Exploratory Study of Efficacy of Ocrelizumab in Autoimmune Encephalitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</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 pilot study is a randomized, double-blind, placebo controlled study of the efficacy of&#xD;
      ocrelizumab in autoimmune encephalitis. Subjects with new diagnosis of autoimmune&#xD;
      encephalitis will be invited to enroll in this study. Subjects will be randomized to receive&#xD;
      ocrelizumab (an anti-CD20 therapy) or matched placebo, and will undergo three infusions over&#xD;
      a six month period. Subjects will complete clinical visits over the study period, during&#xD;
      which safety monitoring and neuropsychological assessments will be performed to assess for&#xD;
      signs of clinical worsening from encephalitis. The primary outcome of this study is the&#xD;
      proportion of patients who fail to complete the twelve month period without clinical&#xD;
      worsening, as defined by the protocol. Subjects who experience early clinical worsening&#xD;
      during the study may be offered open-label treatment with ocrelizumab at the discretion of&#xD;
      the investigators.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Failed to meet target enrollment and study was discontinued&#xD;
  </why_stopped>
  <start_date type="Actual">January 22, 2019</start_date>
  <completion_date type="Actual">October 2, 2020</completion_date>
  <primary_completion_date type="Actual">October 2, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants Who Had Clinical Worsening</measure>
    <time_frame>12 months</time_frame>
    <description>The number of participants who had clinical worsening within 12 months.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Treatment Failure</measure>
    <time_frame>12 months</time_frame>
    <description>Definition of clinical worsening (treatment failure):&#xD;
Clinician or patient/caregiver perception of clinical decline&#xD;
Worsening of patient/family reported IADL (by one point or more)&#xD;
One of the following additional features:&#xD;
Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st deviation)&#xD;
Other clinical worsening leading to hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months</measure>
    <time_frame>Baseline, 6 month</time_frame>
    <description>Change in TFLS T-score (Texas Functional Living Scale) scores at 6 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).&#xD;
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.&#xD;
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.&#xD;
Change in TFLS T-score was used in this study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months</measure>
    <time_frame>Baseline, 12 months</time_frame>
    <description>Change in TFLS T-score (Texas Functional Living Scale) scores at 12 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).&#xD;
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.&#xD;
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.&#xD;
Change in TFLS T-score was used in this study</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Autoimmune Encephalitis</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Placebo Arm</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Saline will be used as the matching placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ocrelizumab</intervention_name>
    <description>Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>This will be the matching placebo used in the study.</description>
    <arm_group_label>Treatment Placebo Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18 or greater&#xD;
&#xD;
          2. Able to obtain informed consent from patient or appropriate designee&#xD;
&#xD;
          3. Possible autoimmune encephalitis as defined by Table 1:&#xD;
&#xD;
               1. Reasonable exclusion of alternative causes&#xD;
&#xD;
               2. Subacute onset (&lt; 3 months) of memory deficits, altered consciousness, and/or&#xD;
                  psychiatric symptoms&#xD;
&#xD;
               3. One or more of the following:&#xD;
&#xD;
                    -  CSF (cerebrospinal fluid) pleocytosis (&gt;5 cells/µl corrected, if necessary,&#xD;
                       for traumatic lumbar puncture)&#xD;
&#xD;
                    -  EEG (electroencephalogram) with epileptiform or focal slow wave&#xD;
                       abnormalities involving temporal lobes&#xD;
&#xD;
                    -  Brain abnormalities on T2/FLAIR MRI restricted to the mesial temporal&#xD;
                       (limbic) lobes&#xD;
&#xD;
                    -  Associated dyskinesias (faciobrachial dystonic movements or orofacial&#xD;
                       dyskinesias)&#xD;
&#xD;
          4. Completed initial treatment with iv steroids (at least 3000mg solumedrol) and plasma&#xD;
             exchange (at least 3 exchanges) within the past 8 weeks&#xD;
&#xD;
          5. Presence of one (or more) of the following autoantibodies in serum or CSF&#xD;
&#xD;
               -  NMDA receptor&#xD;
&#xD;
               -  LGI1&#xD;
&#xD;
               -  CASPR2&#xD;
&#xD;
               -  DPPX&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior immunosuppression treatment in past year (other than steroids, intravenous&#xD;
             immunoglobulin and plasma exchange)&#xD;
&#xD;
          2. Active malignancy requiring chemotherapy&#xD;
&#xD;
          3. Pregnancy&#xD;
&#xD;
          4. Evidence of active hepatitis or tuberculosis infection&#xD;
&#xD;
          5. Medical condition that (in investigators opinion) precludes the use of ocrelizumab&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steven Vernino, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UT Southwestern Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UT Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20.</citation>
    <PMID>26906964</PMID>
  </reference>
  <reference>
    <citation>Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65. doi: 10.1016/S1474-4422(12)70310-1. Epub 2013 Jan 3.</citation>
    <PMID>23290630</PMID>
  </reference>
  <reference>
    <citation>Dubey D, Sawhney A, Greenberg B, Lowden A, Warnack W, Khemani P, Stuve O, Vernino S. The spectrum of autoimmune encephalopathies. J Neuroimmunol. 2015 Oct 15;287:93-7. doi: 10.1016/j.jneuroim.2015.08.014. Epub 2015 Aug 28.</citation>
    <PMID>26439968</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>February 5, 2019</study_first_submitted>
  <study_first_submitted_qc>February 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <results_first_submitted>August 25, 2021</results_first_submitted>
  <results_first_submitted_qc>September 21, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">October 19, 2021</results_first_posted>
  <last_update_submitted>September 21, 2021</last_update_submitted>
  <last_update_submitted_qc>September 21, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Steven Vernino</investigator_full_name>
    <investigator_title>PROFESSOR</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Encephalitis</mesh_term>
    <mesh_term>Autoimmune Diseases of the Nervous System</mesh_term>
    <mesh_term>Hashimoto Disease</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>Yes</sharing_ipd>
  </patient_data>
  <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>March 21, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/28/NCT03835728/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Failed to meet target enrollment and study was discontinued</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Treatment Arm</title>
          <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
        </group>
        <group group_id="P2">
          <title>Treatment Placebo Arm</title>
          <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment Arm</title>
          <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
        </group>
        <group group_id="B2">
          <title>Treatment Placebo Arm</title>
          <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="1"/>
            <count group_id="B3" value="3"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <title>Age</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47.5" lower_limit="25" upper_limit="70"/>
                    <measurement group_id="B2" value="44" lower_limit="44" upper_limit="44"/>
                    <measurement group_id="B3" value="44" lower_limit="25" upper_limit="70"/>
                  </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="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" 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="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Encephalitis antibody</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>NMDAR Ab</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LGI1 Ab</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Who Had Clinical Worsening</title>
        <description>The number of participants who had clinical worsening within 12 months.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
          </group>
          <group group_id="O2">
            <title>Treatment Placebo Arm</title>
            <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Had Clinical Worsening</title>
          <description>The number of participants who had clinical worsening within 12 months.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Treatment Failure</title>
        <description>Definition of clinical worsening (treatment failure):&#xD;
Clinician or patient/caregiver perception of clinical decline&#xD;
Worsening of patient/family reported IADL (by one point or more)&#xD;
One of the following additional features:&#xD;
Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st deviation)&#xD;
Other clinical worsening leading to hospitalization</description>
        <time_frame>12 months</time_frame>
        <population>There were no treatment failures in the treatment arm. Thus, there was no data for this secondary outcome measure in the treatment arm</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
          </group>
          <group group_id="O2">
            <title>Treatment Placebo Arm</title>
            <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Treatment Failure</title>
          <description>Definition of clinical worsening (treatment failure):&#xD;
Clinician or patient/caregiver perception of clinical decline&#xD;
Worsening of patient/family reported IADL (by one point or more)&#xD;
One of the following additional features:&#xD;
Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st deviation)&#xD;
Other clinical worsening leading to hospitalization</description>
          <population>There were no treatment failures in the treatment arm. Thus, there was no data for this secondary outcome measure in the treatment arm</population>
          <units>weeks</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months</title>
        <description>Change in TFLS T-score (Texas Functional Living Scale) scores at 6 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).&#xD;
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.&#xD;
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.&#xD;
Change in TFLS T-score was used in this study</description>
        <time_frame>Baseline, 6 month</time_frame>
        <population>Participant in placebo arm met study endpoint prior to 6 month outcome measure so change in TFLS score at 6 months was not analyzable for efficacy purposes.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
          </group>
          <group group_id="O2">
            <title>Treatment Placebo Arm</title>
            <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months</title>
          <description>Change in TFLS T-score (Texas Functional Living Scale) scores at 6 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).&#xD;
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.&#xD;
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.&#xD;
Change in TFLS T-score was used in this study</description>
          <population>Participant in placebo arm met study endpoint prior to 6 month outcome measure so change in TFLS score at 6 months was not analyzable for efficacy purposes.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.75" lower_limit="3" upper_limit="22.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months</title>
        <description>Change in TFLS T-score (Texas Functional Living Scale) scores at 12 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).&#xD;
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.&#xD;
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.&#xD;
Change in TFLS T-score was used in this study</description>
        <time_frame>Baseline, 12 months</time_frame>
        <population>Participant in placebo arm met study endpoint prior to 6 month outcome measure so change in TFLS score at 12 months was not analyzable for efficacy purposes.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
          </group>
          <group group_id="O2">
            <title>Treatment Placebo Arm</title>
            <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months</title>
          <description>Change in TFLS T-score (Texas Functional Living Scale) scores at 12 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).&#xD;
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.&#xD;
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.&#xD;
Change in TFLS T-score was used in this study</description>
          <population>Participant in placebo arm met study endpoint prior to 6 month outcome measure so change in TFLS score at 12 months was not analyzable for efficacy purposes.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.5" lower_limit="3" upper_limit="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment Arm</title>
          <description>Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.&#xD;
Ocrelizumab: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.</description>
        </group>
        <group group_id="E2">
          <title>Treatment Placebo Arm</title>
          <description>Saline will be used as the matching placebo&#xD;
Saline: This will be the matching placebo used in the study.</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="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </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="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Elevated transaminases</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizures</sub_title>
                <description>related to encephalitis - unrelated to treatment</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>
    <limitations_and_caveats>Early termination of trial due to inadequate recruitment. Small numbers of subjects prevents definitive analysis of results</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Steven Vernino</name_or_title>
      <organization>UT Southwestern, Dept of Neurology</organization>
      <phone>214-645-8800</phone>
      <email>steven.vernino@utsouthwestern.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/NCT03835728
org study id: STU-2018-0185
nct id: NCT03835728
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This pilot study is a randomized, double-blind, placebo controlled study of the efficacy of
      ocrelizumab in autoimmune encephalitis. Subjects with new diagnosis of autoimmune
      encephalitis will be invited to enroll in this study. Subjects will be randomized to receive
      ocrelizumab (an anti-CD20 therapy) or matched placebo, and will undergo three infusions over
      a six month period. Subjects will complete clinical visits over the study period, during
      which safety monitoring and neuropsychological assessments will be performed to assess for
      signs of clinical worsening from encephalitis. The primary outcome of this study is the
      proportion of patients who fail to complete the twelve month period without clinical
      worsening, as defined by the protocol. Subjects who experience early clinical worsening
      during the study may be offered open-label treatment with ocrelizumab at the discretion of
      the investigators.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Participants Who Had Clinical Worsening
time frame: 12 months
description: The number of participants who had clinical worsening within 12 months.
measure: Time to Treatment Failure
time frame: 12 months
description: Definition of clinical worsening (treatment failure):
Clinician or patient/caregiver perception of clinical decline
Worsening of patient/family reported IADL (by one point or more)
One of the following additional features:
Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st deviation)
Other clinical worsening leading to hospitalization
measure: Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months
time frame: Baseline, 6 month
description: Change in TFLS T-score (Texas Functional Living Scale) scores at 6 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.
Change in TFLS T-score was used in this study
measure: Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months
time frame: Baseline, 12 months
description: Change in TFLS T-score (Texas Functional Living Scale) scores at 12 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).
Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.
Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.
Change in TFLS T-score was used in this study
arm group label: Treatment Arm
arm group type: Active Comparator
description: Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.
arm group label: Treatment Placebo Arm
arm group type: Placebo Comparator
description: Saline will be used as the matching placebo
intervention type: Drug
intervention name: Ocrelizumab
description: Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.
arm group label: Treatment Arm
intervention type: Drug
intervention name: Saline
description: This will be the matching placebo used in the study.
arm group label: Treatment Placebo Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Steven Vernino, MD, PhD
role: Principal Investigator
affiliation: UT Southwestern Medical Center
facility: 
country: United States
citation: Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20.
PMID: 26906964
citation: Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65. doi: 10.1016/S1474-4422(12)70310-1. Epub 2013 Jan 3.
PMID: 23290630
citation: Dubey D, Sawhney A, Greenberg B, Lowden A, Warnack W, Khemani P, Stuve O, Vernino S. The spectrum of autoimmune encephalopathies. J Neuroimmunol. 2015 Oct 15;287:93-7. doi: 10.1016/j.jneuroim.2015.08.014. Epub 2015 Aug 28.
PMID: 26439968
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Steven Vernino
investigator title: PROFESSOR
mesh term: Encephalitis
mesh term: Autoimmune Diseases of the Nervous System
mesh term: Hashimoto Disease
mesh term: Ocrelizumab
sharing ipd: Yes
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early termination of trial due to inadequate recruitment. Small numbers of subjects prevents definitive analysis of results
point of contact: 