<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/NCT03283826</url>
  </required_header>
  <id_info>
    <org_study_id>ATA188-MS-101</org_study_id>
    <nct_id>NCT03283826</nct_id>
  </id_info>
  <brief_title>Phase 1/2 Study to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis</brief_title>
  <acronym>EMBOLD</acronym>
  <official_title>A Phase 1/2, Two-part, Open-label Dose-escalation and Double-blind, Placebo-controlled Dose-expansion Study With an Open-label Extension to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Atara Biotherapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Atara Biotherapeutics</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of ATA188 as a&#xD;
      monotherapy in Parts 1 and 2, to determine the recommended Part 2 dose (RP2D) of ATA188 as&#xD;
      monotherapy in Part 1, and to evaluate the effect of ATA188 treatment on clinical disability,&#xD;
      as assessed by confirmed Expanded Disability Status Scale (EDSS) improvement at 12 months in&#xD;
      Part 2 in participants with progressive forms of multiple sclerosis (MS) (primary progressive&#xD;
      multiple sclerosis [PPMS] and secondary progressive multiple sclerosis [SPMS]).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter, 2 part study in adult participants with progressive forms of MS&#xD;
      (PPMS/SPMS) with an open-label, single-arm, sequential dose-escalation period (Part 1) and a&#xD;
      double-blind, randomized, placebo-controlled dose-expansion period (Part 2) followed by&#xD;
      open-label extension (OLE) period. Part 2 and the OLE have been initiated by the sponsor's&#xD;
      discretion based on a review of data from the dose-escalation cohorts.&#xD;
&#xD;
      This study will evaluate the safety and efficacy of ATA188 administered by intravenous (IV)&#xD;
      infusion. ATA188 will be selected for each participant based on matching 2 or more human&#xD;
      leukocyte antigen (HLA) alleles shared between ATA188 and the participant, at least 1 of&#xD;
      which is a HLA-restricting allele.&#xD;
&#xD;
      In Part 1, participants received 2 cycles of ATA188 and entered 12 months follow-up period&#xD;
      after the last dose of ATA188. Participants who completed at least the first year of the&#xD;
      dose-escalation period and were active in the study have entered the OLE period. In OLE&#xD;
      period, participants will receive the same RP2D assigned to Part 2 participants at the time&#xD;
      of the Part 1 participant's first dose in each year of the OLE. In OLE period, participants&#xD;
      will receive 1 cycle of ATA188 treatment every 12 months (Q12M) for up to 4 years (ie, Years&#xD;
      2 to 5). Otherwise, end of study (EOS) visit will be conducted at 24 months after Cycle 1 Day&#xD;
      1.&#xD;
&#xD;
      In Part 2, participants will be randomized in 1:1 ratio to receive ATA188 at the RP2D or&#xD;
      matching placebo, stratified by progressive MS diagnosis (PPMS vs SPMS) and any prior&#xD;
      exposure to anti-CD20 therapy (yes vs no). Participants will receive 2 cycles of ATA188 at&#xD;
      the RP2D or matching placebo and will be followed for at least 12 months after the first dose&#xD;
      of study drug (ie, Year 1). In second year (Year 2), participants who received placebo in&#xD;
      Year 1 will receive 2 cycles of ATA188 at the RP2D assigned at randomization and participants&#xD;
      who received ATA188 at the RP2D in Year 1 will receive 1 cycle of ATA188 (at the RP2D&#xD;
      assigned at randomization) and 1 cycle of placebo to maintain the blind. Participants who&#xD;
      complete Year 2 will enter the OLE period to receive ATA188 Q12M for up to 3 years (ie, Years&#xD;
      3 to 5) at the RP2D that was last selected by the sponsor for Part 2. The end of study visit&#xD;
      will be scheduled at 5 years (60 months) after the first dose of study drug (ie, Cycle 1 Day&#xD;
      1).&#xD;
&#xD;
      Based on interim analysis, the recruitment for Parts 1and 2 have completed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 19, 2017</start_date>
  <completion_date type="Anticipated">September 2027</completion_date>
  <primary_completion_date type="Anticipated">July 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1: Incidence of adverse events</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1: Incidence of clinically significant changes in laboratory tests, electrocardiograms (ECGs), and vital signs</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1: Recommended Part 2 dose of ATA188 monotherapy</measure>
    <time_frame>Day 1 to Day 35 of Cycle 1 for each participant in dose escalation part (approximately 1 year)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2: Percentage of participants with confirmed expanded disability status scale (EDSS) improvement at 12 months</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part 1: Change from baseline in EDSS score</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Percentage of participants with confirmed EDSS improvement at 15 months</measure>
    <time_frame>At 15 months after the first dose of study drug</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Percentage of participants with sustained disability improvement (SDI; ie, confirmed EDSS improvement or 20% decrease in timed 25-foot walk [T25W]) at 12 months</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Percentage of participants with SDI at 15 months</measure>
    <time_frame>At 15 months after the first dose of study drug</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Change from baseline in immunoglobulin G (IgG) index</measure>
    <time_frame>At 9 months after the first dose of study drug</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Change from baseline in cervical spinal cord volume on MRI scans</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change from baseline in whole brain volume on MRI scans</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change from baseline in number of Gd-enhancing and new or enlarging T2 lesions on brain MRI scans</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change from baseline in IgG production</measure>
    <time_frame>At 12 months after the first dose of study drug</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">134</enrollment>
  <condition>Primary Progressive Multiple Sclerosis</condition>
  <condition>Secondary Progressive Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>ATA188</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in Parts 1 and 2 will receive ATA188 intravenously as described in the Detailed Description.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants in Part 2 will receive placebo matching to ATA188 intravenously as described in the Detailed Description (i.e., will receive placebo only in the first year, and thereafter will receive ATA188 for the remainder of the study).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ATA188</intervention_name>
    <description>ATA188 is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ progressive multiple sclerosis.</description>
    <arm_group_label>ATA188</arm_group_label>
    <other_name>Epstein-Barr Virus-directed cytotoxic T lymphocytes (CTLs)</other_name>
    <other_name>EBV-CTLs</other_name>
    <other_name>EBV-targeted T-cell</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo matching to ATA188</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  For Part 1: History of progressive forms of MS (PPMS or SPMS), as defined by the 2010&#xD;
             Revised McDonald criteria for the diagnosis of MS&#xD;
&#xD;
          -  For Part 1: 18 to &lt; 66 years of age&#xD;
&#xD;
          -  For Part 1: EDSS scores of 3.0 to 7.0. Participants with EDSS scores of 6.5 to 7.0&#xD;
             must retain measurable upper limb function as assessed by the 9-hole Peg Test (9HPT).&#xD;
&#xD;
          -  For Part 2: Current diagnosis of a progressive form of MS (PPMS or SPMS) as defined by&#xD;
             the 2017 Revised McDonald criteria&#xD;
&#xD;
          -  For Part 2:18 to &lt; 61 years of age&#xD;
&#xD;
          -  For Part 2:EDSS scores of 3.0 to 6.5&#xD;
&#xD;
          -  Positive EBV serology&#xD;
&#xD;
          -  Willing and able to provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Clinical relapse as follows: For Part 1: Active clinical relapse between providing&#xD;
             informed consent and the first dose of study drug. For Part 2: Documented clinical&#xD;
             and/or radiological relapse for 2 years prior to screening, including gadolinium&#xD;
             (Gd)-enhancing lesion(s) on any brain MRI scans available during this period (A&#xD;
             participant will also be considered ineligible if any clinical and/or radiological&#xD;
             relapse is reported between screening and the first dose of study drug.)&#xD;
&#xD;
          -  Concurrent serious uncontrolled or unresolved medical condition, such as infection,&#xD;
             limiting protocol compliance or exposing the subject to unacceptable risk&#xD;
&#xD;
          -  Positive serology and/or nucleic acid testing (NAT) for human immunodeficiency virus&#xD;
             (HIV), active hepatitis B virus (HBV) infection or carrier status for HBV, active&#xD;
             hepatitis C virus (HCV) infection&#xD;
&#xD;
          -  For Part 1: Positive serology for syphilis or human T cell lymphotrophic virus I/II&#xD;
&#xD;
          -  Uncontrolled psychosis, uncontrolled depression or suicide risk, substance dependence,&#xD;
             or any other psychiatric condition that may compromise the ability to participate in&#xD;
             this trial&#xD;
&#xD;
          -  Clinically significant abnormalities of full blood count, renal function, or hepatic&#xD;
             function&#xD;
&#xD;
          -  Any contraindication to MRI and/or Gd, eg., any object that is reactive to strong&#xD;
             static magnetic, pulsed-gradient fields including any metallic fragments or foreign&#xD;
             body (eg, aneurysm clip[s], pacemakers, electronic implants, shunts)&#xD;
&#xD;
          -  Any history of cancer (as exceptions, successfully treated non-melanoma skin cancer or&#xD;
             carcinoma in situ of the cervix with a &lt; 5% chance of recurrence within 12 months of&#xD;
             providing informed consent are allowed.)&#xD;
&#xD;
          -  Prior therapy with corticosteroids (within 2 weeks before Cycle 1 Day 1)&#xD;
&#xD;
          -  Prior therapy (30 days) B-cell depleting agent (eg, anti-CD20 agents such as&#xD;
             ocrelizumab); participant must be progressing despite therapy to be eligible&#xD;
&#xD;
          -  For Part 1: Prior therapy (6 half-lives or 30 days whichever is longer) with&#xD;
             cladribine, glatiramer acetate, interferon β, dimethyl fumarate, methotrexate,&#xD;
             azathioprine, cyclosporine, fingolimod, natalizumab, teriflunomide, mitoxantrone,&#xD;
             cyclophosphamide, any other immunosuppressant or cytotoxic therapy (other than&#xD;
             steroids), antithymocyte globulin or similar anti-T-cell antibody therapy, or any&#xD;
             other investigational product&#xD;
&#xD;
          -  For Part 1: Any previous treatment with alemtuzumab, ablative stem cell transplant, or&#xD;
             EBV T-cell therapy&#xD;
&#xD;
          -  For Part 2: Prior therapy (6 half-lives or 30 days whichever is longer) with IV&#xD;
             immunoglobin, plasmapheresis, Bruton's tyrosine kinase inhibitors, all sphingosine&#xD;
             1-phosphate receptor modulators (eg, fingolimod), glatiramer acetate, interferon β,&#xD;
             nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators (eg, dimethyl fumarate),&#xD;
             methotrexate, azathioprine, cyclosporine, natalizumab, teriflunomide, mitoxantrone,&#xD;
             cyclophosphamide, any other immunosuppressant or cytotoxic therapy (other than&#xD;
             steroids), antithymocyte globulin or similar anti-T-cell antibody therapy, or any&#xD;
             other investigational product&#xD;
&#xD;
          -  For Part 2: Any previous treatment with cladribine, alemtuzumab, ablative stem cell&#xD;
             transplant, or EBV T-cell therapy&#xD;
&#xD;
          -  Unresolved reactions from previous therapies that may, in the investigator's opinion,&#xD;
             impact the safety of the participant or the conduct of this study&#xD;
&#xD;
          -  Unwilling to use protocol specified contraceptive methods&#xD;
&#xD;
          -  Women who are breastfeeding&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Inability or unwillingness to comply with study procedures&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kiren Kresa-Reahl, MD</last_name>
    <role>Study Director</role>
    <affiliation>Atara Biotherapeutics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Diego</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente MS Clinic Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advanced Neurology</name>
      <address>
        <city>Fort Collins</city>
        <state>Colorado</state>
        <zip>80528</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Associates, PA-Maitland</name>
      <address>
        <city>Maitland</city>
        <state>Florida</state>
        <zip>32751</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida, Morsani College of Medicine</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fort Wayne Neurological Center</name>
      <address>
        <city>Fort Wayne</city>
        <state>Indiana</state>
        <zip>46825</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Medical Center KUMC - Multiple Sclerosis MS Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ochsner Clinic Foundation</name>
      <address>
        <city>New Orleans</city>
        <state>Louisiana</state>
        <zip>70121</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dragonfly Research</name>
      <address>
        <city>Wellesley</city>
        <state>Massachusetts</state>
        <zip>02481</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University in St. Louis</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dent Neurologic Institute</name>
      <address>
        <city>Amherst</city>
        <state>New York</state>
        <zip>14226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center-The Neurological Institute of New York</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester Medical Center - URMC</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>PMG Research of Piedmont Healthcare</name>
      <address>
        <city>Mooresville</city>
        <state>North Carolina</state>
        <zip>28117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104-5127</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Premier Neurology P.C.</name>
      <address>
        <city>Greer</city>
        <state>South Carolina</state>
        <zip>29650</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advanced Neurosciences Institute ANI - Franklin</name>
      <address>
        <city>Franklin</city>
        <state>Tennessee</state>
        <zip>37064</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt Comprehensive Multiple Sclerosis Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas Health Science Center at Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MS Center of Greater Washington</name>
      <address>
        <city>Vienna</city>
        <state>Virginia</state>
        <zip>22182</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Inland Northwest Research LLC</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Liverpool Hospital</name>
      <address>
        <city>Liverpool</city>
        <state>New South Wales</state>
        <zip>2170</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Brisbane and Women's Hospital</name>
      <address>
        <city>Brisbane</city>
        <state>Queensland</state>
        <zip>4029</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Griffith University, School of Medicine</name>
      <address>
        <city>Southport</city>
        <state>Queensland</state>
        <zip>4222</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fraser Health Multiple Sclerosis Clinic</name>
      <address>
        <city>Burnaby</city>
        <state>British Columbia</state>
        <zip>V5G 2X6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Unity Health Toronto/St. Michael's Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5B1W8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Recherche Sepmus Inc.</name>
      <address>
        <city>Greenfield Park</city>
        <state>Quebec</state>
        <zip>J4V2J2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR, Khanna R. Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult Scler. 2014 Oct;20(11):1541-4. doi: 10.1177/1352458514521888. Epub 2014 Feb 3.</citation>
    <PMID>24493474</PMID>
  </reference>
  <reference>
    <citation>Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunology. 2017 Jan 20;6(1):e126. doi: 10.1038/cti.2016.87. eCollection 2017 Jan. Erratum In: Clin Transl Immunology. 2017 Jun 16;6(6):e147.</citation>
    <PMID>28197337</PMID>
  </reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>September 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>April 24, 2023</last_update_submitted>
  <last_update_submitted_qc>April 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Multiple Sclerosis (MS)</keyword>
  <keyword>Primary Progressive Multiple Sclerosis</keyword>
  <keyword>Secondary Progressive Multiple Sclerosis</keyword>
  <keyword>Epstein-Barr Virus (EBV)</keyword>
  <keyword>EBV-associated Multiple Sclerosis</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Central Nervous System</keyword>
  <keyword>Autoimmune Disease</keyword>
  <keyword>Autoimmunity</keyword>
  <keyword>Demyelination</keyword>
  <keyword>Cell Therapy</keyword>
  <keyword>T-cell</keyword>
  <keyword>Allogeneic</keyword>
  <keyword>EBV viremia</keyword>
  <keyword>Off-the-shelf (T cells)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Chronic Progressive</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03283826
org study id: ATA188-MS-101
nct id: NCT03283826
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate the safety and tolerability of ATA188 as a
      monotherapy in Parts 1 and 2, to determine the recommended Part 2 dose (RP2D) of ATA188 as
      monotherapy in Part 1, and to evaluate the effect of ATA188 treatment on clinical disability,
      as assessed by confirmed Expanded Disability Status Scale (EDSS) improvement at 12 months in
      Part 2 in participants with progressive forms of multiple sclerosis (MS) (primary progressive
      multiple sclerosis [PPMS] and secondary progressive multiple sclerosis [SPMS]).
This is a multicenter, 2 part study in adult participants with progressive forms of MS
      (PPMS/SPMS) with an open-label, single-arm, sequential dose-escalation period (Part 1) and a
      double-blind, randomized, placebo-controlled dose-expansion period (Part 2) followed by
      open-label extension (OLE) period. Part 2 and the OLE have been initiated by the sponsor's
      discretion based on a review of data from the dose-escalation cohorts.

      This study will evaluate the safety and efficacy of ATA188 administered by intravenous (IV)
      infusion. ATA188 will be selected for each participant based on matching 2 or more human
      leukocyte antigen (HLA) alleles shared between ATA188 and the participant, at least 1 of
      which is a HLA-restricting allele.

      In Part 1, participants received 2 cycles of ATA188 and entered 12 months follow-up period
      after the last dose of ATA188. Participants who completed at least the first year of the
      dose-escalation period and were active in the study have entered the OLE period. In OLE
      period, participants will receive the same RP2D assigned to Part 2 participants at the time
      of the Part 1 participant's first dose in each year of the OLE. In OLE period, participants
      will receive 1 cycle of ATA188 treatment every 12 months (Q12M) for up to 4 years (ie, Years
      2 to 5). Otherwise, end of study (EOS) visit will be conducted at 24 months after Cycle 1 Day
      1.

      In Part 2, participants will be randomized in 1:1 ratio to receive ATA188 at the RP2D or
      matching placebo, stratified by progressive MS diagnosis (PPMS vs SPMS) and any prior
      exposure to anti-CD20 therapy (yes vs no). Participants will receive 2 cycles of ATA188 at
      the RP2D or matching placebo and will be followed for at least 12 months after the first dose
      of study drug (ie, Year 1). In second year (Year 2), participants who received placebo in
      Year 1 will receive 2 cycles of ATA188 at the RP2D assigned at randomization and participants
      who received ATA188 at the RP2D in Year 1 will receive 1 cycle of ATA188 (at the RP2D
      assigned at randomization) and 1 cycle of placebo to maintain the blind. Participants who
      complete Year 2 will enter the OLE period to receive ATA188 Q12M for up to 3 years (ie, Years
      3 to 5) at the RP2D that was last selected by the sponsor for Part 2. The end of study visit
      will be scheduled at 5 years (60 months) after the first dose of study drug (ie, Cycle 1 Day
      1).

      Based on interim analysis, the recruitment for Parts 1and 2 have completed.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Part 1: Incidence of adverse events
time frame: At 12 months after the first dose of study drug
measure: Part 1: Incidence of clinically significant changes in laboratory tests, electrocardiograms (ECGs), and vital signs
time frame: At 12 months after the first dose of study drug
measure: Part 1: Recommended Part 2 dose of ATA188 monotherapy
time frame: Day 1 to Day 35 of Cycle 1 for each participant in dose escalation part (approximately 1 year)
measure: Part 2: Percentage of participants with confirmed expanded disability status scale (EDSS) improvement at 12 months
time frame: At 12 months after the first dose of study drug
measure: Part 1: Change from baseline in EDSS score
time frame: At 12 months after the first dose of study drug
measure: Part 2: Percentage of participants with confirmed EDSS improvement at 15 months
time frame: At 15 months after the first dose of study drug
measure: Part 2: Percentage of participants with sustained disability improvement (SDI; ie, confirmed EDSS improvement or 20% decrease in timed 25-foot walk [T25W]) at 12 months
time frame: At 12 months after the first dose of study drug
measure: Part 2: Percentage of participants with SDI at 15 months
time frame: At 15 months after the first dose of study drug
measure: Part 2: Change from baseline in immunoglobulin G (IgG) index
time frame: At 9 months after the first dose of study drug
measure: Change from baseline in cervical spinal cord volume on MRI scans
time frame: At 12 months after the first dose of study drug
measure: Change from baseline in whole brain volume on MRI scans
time frame: At 12 months after the first dose of study drug
measure: Change from baseline in number of Gd-enhancing and new or enlarging T2 lesions on brain MRI scans
time frame: At 12 months after the first dose of study drug
measure: Change from baseline in IgG production
time frame: At 12 months after the first dose of study drug
arm group label: ATA188
arm group type: Experimental
description: Participants in Parts 1 and 2 will receive ATA188 intravenously as described in the Detailed Description.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants in Part 2 will receive placebo matching to ATA188 intravenously as described in the Detailed Description (i.e., will receive placebo only in the first year, and thereafter will receive ATA188 for the remainder of the study).
intervention type: Biological
intervention name: ATA188
description: ATA188 is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ progressive multiple sclerosis.
arm group label: ATA188
other name: Epstein-Barr Virus-directed cytotoxic T lymphocytes (CTLs)
other name: EBV-CTLs
other name: EBV-targeted T-cell
intervention type: Drug
intervention name: Placebo
description: Placebo matching to ATA188
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Kiren Kresa-Reahl, MD
role: Study Director
affiliation: Atara Biotherapeutics
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country: Australia
country: Canada
country: United States
citation: Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR, Khanna R. Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult Scler. 2014 Oct;20(11):1541-4. doi: 10.1177/1352458514521888. Epub 2014 Feb 3.
PMID: 24493474
citation: Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunology. 2017 Jan 20;6(1):e126. doi: 10.1038/cti.2016.87. eCollection 2017 Jan. Erratum In: Clin Transl Immunology. 2017 Jun 16;6(6):e147.
PMID: 28197337
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Chronic Progressive
mesh term: Sclerosis
sharing ipd: No