<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/NCT04410991</url>
  </required_header>
  <id_info>
    <org_study_id>EFC16034</org_study_id>
    <secondary_id>U1111-1238-1373</secondary_id>
    <nct_id>NCT04410991</nct_id>
  </id_info>
  <brief_title>Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168)</brief_title>
  <acronym>GEMINI 2</acronym>
  <official_title>A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sanofi</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>
      Primary Objective:&#xD;
&#xD;
      To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide&#xD;
      (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with&#xD;
      relapsing forms of MS&#xD;
&#xD;
      Secondary Objective:&#xD;
&#xD;
      To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability&#xD;
      progression, MRI lesions, cognitive performance and quality of life To evaluate the safety&#xD;
      and tolerability of daily SAR442168 To evaluate pharmacodynamics (PD) of SAR442168&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study duration will vary per participant in this event driven trial with a treatment duration&#xD;
      of approximately 18 to 36 months. Participants completing the study will be offered to&#xD;
      participate in a long term safety study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 11, 2020</start_date>
  <completion_date type="Anticipated">April 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2024</primary_completion_date>
  <phase>Phase 3</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses</measure>
    <time_frame>Up to approximately 36 months</time_frame>
    <description>Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to onset of confirmed disability worsening confirmed over at least 6 months</measure>
    <time_frame>Up to approximately 36 months</time_frame>
    <description>ime to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows:&#xD;
increase of ≥1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0 OR&#xD;
increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5 OR&#xD;
increase of ≥0.5 point from the baseline EDSS score when the baseline score is &gt;5.5 - 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months</measure>
    <time_frame>Up to 36 approximately months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study</measure>
    <time_frame>From 6 months up to approximately 36 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Number of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the End of study (EOS)</measure>
    <time_frame>From 6 months up to approximately 36 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cognitive function</measure>
    <time_frame>From Baseline up to 36 approximately months</time_frame>
    <description>Change in cognitive function from baseline to the EOS as assessed by the SDMT and CVLT-II where available</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to confirmed disability improvement</measure>
    <time_frame>From Baseline up to approximately 36 months</time_frame>
    <description>Time to confirmed disability improvement (CDI), defined as a ≥1.0 point decrease on the EDSS from the baseline EDSS score confirmed over at least 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change in Brain volume Loss as detected by brain MRI</measure>
    <time_frame>From 6 months up to approximately 36 months</time_frame>
    <description>Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54)</measure>
    <time_frame>From Baseline up to approximately 36 months</time_frame>
    <description>Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events A(Es) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)</measure>
    <time_frame>From screening until end of study approximately 36 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in plasma neurofilament light chain (NfL)</measure>
    <time_frame>From Baseline until end of study up to approximately 36 months -</time_frame>
    <description>Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baselineC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasma Immunoglobulin level</measure>
    <time_frame>From Baseline until end of study up to 36 approximately months</time_frame>
    <description>Changes in serum immunoglobulin level at the EOS compared to baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum chitinase-3 like protein 1 (Chi3L1) -</measure>
    <time_frame>From Baseline until end of study up to approximately 36 months -</time_frame>
    <description>Change in serum Chi3L1 levels at the EOS compared to baseline -</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">900</enrollment>
  <condition>Relapsing Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>SAR442168</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose 1 of oral SAR442168 daily + placebo to match the teriflunomide tablet once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Teriflunomide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oral 14 mg oral teriflunomide + placebo to match the SAR442168 tablet once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolebrutinib</intervention_name>
    <description>Pharmaceutical form: Tablet&#xD;
Route of administration: Oral</description>
    <arm_group_label>SAR442168</arm_group_label>
    <other_name>SAR442168</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Teriflunomide HMR1726</intervention_name>
    <description>Pharmaceutical form: Tablet&#xD;
Route of administration: Oral</description>
    <arm_group_label>Teriflunomide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo to match Tolebrutinib</intervention_name>
    <description>Pharmaceutical form: Tablet&#xD;
Route of administration: Oral</description>
    <arm_group_label>Teriflunomide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo to match Teriflunomide</intervention_name>
    <description>Pharmaceutical form: Tablet&#xD;
Route of administration: Oral</description>
    <arm_group_label>SAR442168</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria :&#xD;
&#xD;
          -  The participant must be 18 to 55 years of age, inclusive, at the time of signing the&#xD;
             informed consent&#xD;
&#xD;
          -  The participant must have been diagnosed with RMS according to the 2017 revision of&#xD;
             the McDonald diagnostic criteria&#xD;
&#xD;
          -  The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first&#xD;
             Screening Visit&#xD;
&#xD;
          -  The participant must have at least 1 of the following prior to screening:&#xD;
&#xD;
               -  ≥1 documented relapse within the previous year OR&#xD;
&#xD;
               -  ≥2 documented relapses within the previous 2 years, OR&#xD;
&#xD;
               -  ≥1 documented Gd enhancing lesion on an MRI scan within the previous year&#xD;
&#xD;
          -  Contraceptive use by men or women should be consistent with local regulations&#xD;
             regarding the methods of contraception for those participating in clinical studies&#xD;
&#xD;
          -  Male participants are eligible to participate if they agree to the following during&#xD;
             the intervention period and until accelerated elimination procedure:&#xD;
&#xD;
               -  Refrain from donating sperm&#xD;
&#xD;
        Plus either:&#xD;
&#xD;
          -  Be abstinent from heterosexual intercourse as their preferred and usual lifestyle&#xD;
             (abstinent on a long term and persistent basis) and agree to remain abstinent OR&#xD;
&#xD;
          -  Must agree to use contraception/barrier as detailed below&#xD;
&#xD;
          -  Agree to use a male condom and should also be advised of the benefit for a female&#xD;
             partner to use a highly effective method of contraception as a condom may break or&#xD;
             leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who&#xD;
             is not currently pregnant&#xD;
&#xD;
             - A female participant is eligible to participate if she is not pregnant or&#xD;
             breastfeeding, and at least one of the following conditions apply:&#xD;
&#xD;
          -  Is not a WOCBP OR&#xD;
&#xD;
          -  Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a&#xD;
             failure rate of &lt;1% per year), preferably with low user dependency during the&#xD;
             intervention period and until accelerated elimination procedure is completed (or for&#xD;
             at least 10 days after the last dose of SAR442168, if the case was unblinded) and&#xD;
             agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the&#xD;
             study and for the same period of time.&#xD;
&#xD;
               -  A WOCBP must have a negative highly sensitive pregnancy test at screening and&#xD;
                  within 24hours before the first dose of study intervention.&#xD;
&#xD;
               -  If a urine test cannot be confirmed as negative (eg, an ambiguous result), a&#xD;
                  serum pregnancy test is required. In such cases, the participant must be excluded&#xD;
                  from participation if the serum pregnancy result is positive.&#xD;
&#xD;
               -  The Investigator is responsible for review of medical history, menstrual history,&#xD;
                  and recent sexual activity to decrease the risk for inclusion of a woman with an&#xD;
                  early undetected pregnancy.&#xD;
&#xD;
               -  The participant must have given written informed consent prior to undertaking any&#xD;
                  study related procedure. This includes consent to comply with the requirements&#xD;
                  and restrictions listed in the informed consent form (ICF) and in this protocol.&#xD;
                  In countries where the legal age of maturity is greater than 18 years, a specific&#xD;
                  ICF for such legally minor participants must also be signed by the participant's&#xD;
                  legally authorized representative&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  The participant has been diagnosed with primary progressive multiplesclerosis (PPMS)&#xD;
             according to the 2017 revision of the McDonald diagnostic criteria or with&#xD;
             nonrelapsing secondary progressive multiplesclerosis (SPMS)&#xD;
&#xD;
          -  The participant has a history of infection or may be at risk for infection including&#xD;
             but not limited to: HIV, transplantation, live attenuated vaccines, progressive&#xD;
             multifocal leukoencephalopathy, tuberculosis, hepatitis B or C, any persistent chronic&#xD;
             or active recurring infection&#xD;
&#xD;
          -  Clinically significant laboratory abnormalities (including evidence of liver injury)&#xD;
             or electrocardiogram abnormalities at Screening.&#xD;
&#xD;
          -  The participant has conditions or situations that would adversely affect participation&#xD;
             in this study, including but not limited to:&#xD;
&#xD;
               -  A short life expectancy due to pre-existing health condition(s) as determined by&#xD;
                  their treating neurologist&#xD;
&#xD;
               -  Medical condition(s) or concomitant disease(s) making them nonevaluable for the&#xD;
                  primary efficacy endpoint or that would adversely affect participation in this&#xD;
                  study, as judged by the Investigator&#xD;
&#xD;
               -  A requirement for concomitant treatment that could bias the primary evaluation&#xD;
&#xD;
          -  The participant has a history of or currently has concomitant medical or clinical&#xD;
             conditions that would adversely affect participation in this study&#xD;
&#xD;
          -  At screening, the participant is positive for hepatitis B surface antigen and/or&#xD;
             hepatitis B core antibody and/or is positive for hepatitis C antibody&#xD;
&#xD;
          -  The participant has any of the following:&#xD;
&#xD;
               -  A bleeding disorder or known platelet dysfunction at any time prior to the&#xD;
                  screening visit&#xD;
&#xD;
               -  A platelet count &lt;150 000/μL at the screening visit&#xD;
&#xD;
          -  The participant has a lymphocyte count below the lower limit of normal (LLN) at the&#xD;
             screening visit&#xD;
&#xD;
          -  The presence of psychiatric disturbance or substance abuse&#xD;
&#xD;
          -  Prior/concomitant therapy&#xD;
&#xD;
          -  The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A&#xD;
             or potent inhibitors of CYP2C8 hepatic enzymes&#xD;
&#xD;
          -  The participant is receiving anticoagulant/antiplatelet therapies&#xD;
&#xD;
          -  The above information is not intended to contain all considerations relevant to a&#xD;
             patient's potential participation in a clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Sciences &amp; Operations</last_name>
    <role>Study Director</role>
    <affiliation>Sanofi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>North Central Neurology Associates, PC-Site Number:8400009</name>
      <address>
        <city>Cullman</city>
        <state>Alabama</state>
        <zip>35058</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Center for Neurology and Spine-Site Number:8400089</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>84018</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Arcadia Neurology Center-Site Number:8400070</name>
      <address>
        <city>Arcadia</city>
        <state>California</state>
        <zip>91006</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Multiple Sclerosis Center of California-Site Number:8400135</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Harbor UCLA-Site Number:8400088</name>
      <address>
        <city>Torrance</city>
        <state>California</state>
        <zip>90502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mountain Neurological Research Center, Inc.-Site Number:8400128</name>
      <address>
        <city>Basalt</city>
        <state>Colorado</state>
        <zip>81621</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advanced Neurosciences Research-Site Number:8400025</name>
      <address>
        <city>Fort Collins</city>
        <state>Colorado</state>
        <zip>80528</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>South Florida Neurology Associates-Site Number:8400029</name>
      <address>
        <city>Boca Raton</city>
        <state>Florida</state>
        <zip>33487</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida Health-Site Number:8400159</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Associates, PA-Site Number:8400004</name>
      <address>
        <city>Maitland</city>
        <state>Florida</state>
        <zip>32761</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami-Site Number:8400063</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Infinity Clinical Research-Site Number:8400008</name>
      <address>
        <city>Sunrise</city>
        <state>Florida</state>
        <zip>33351</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida-Site Number:8400006</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Meridian Clinical Research-Site Number:8400003</name>
      <address>
        <city>Savannah</city>
        <state>Georgia</state>
        <zip>31406</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Consultants In Neurology-Site Number:8400011</name>
      <address>
        <city>Northbrook</city>
        <state>Illinois</state>
        <zip>60062</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Prairie Education and Research Cooperative-Site Number:8400071</name>
      <address>
        <city>Springfield</city>
        <state>Illinois</state>
        <zip>62701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fort Wayne Neurological Center-Site Number:8400039</name>
      <address>
        <city>Fort Wayne</city>
        <state>Indiana</state>
        <zip>46804</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHI Saint Joseph Medical Group Neurology-Site Number:8400110</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40509</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kentucky-Site Number:8400106</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norton Neurology MS Services-Site Number:8400127</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The NeuroMedical Center-Site Number:8400057</name>
      <address>
        <city>Baton Rouge</city>
        <state>Louisiana</state>
        <zip>70810</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>International Neurorehabilitation Institute-Site Number:8400034</name>
      <address>
        <city>Lutherville-Timonium</city>
        <state>Maryland</state>
        <zip>21093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wayne State University-Site Number:8400046</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Minneapolis Clinic of Neurology-Site Number:8400051</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55422</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Luke's Hospital-Site Number:8400153</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Omaha Family Physicians-Site Number:8400139</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Of Nebraska-Site Number:8400129</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68198</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hackensack University Hospital-Site Number:8400047</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of New Mexico-Site Number:8400032</name>
      <address>
        <city>Albuquerque</city>
        <state>New Mexico</state>
        <zip>87131</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>South Shore Neurologic Associates-Site Number:8400100</name>
      <address>
        <city>Patchogue</city>
        <state>New York</state>
        <zip>11772</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novant Health Multiple Sclerosis Care Center - South Park-Site Number:8400120</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Meridian Clinical Research, LLC-Site Number:8400005</name>
      <address>
        <city>Raleigh</city>
        <state>North Carolina</state>
        <zip>27607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sanford Brain &amp; Spine Center-Site Number:8400126</name>
      <address>
        <city>Fargo</city>
        <state>North Dakota</state>
        <zip>58103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dayton Center for Neurological Disorders-Site Number:8400081</name>
      <address>
        <city>Centerville</city>
        <state>Ohio</state>
        <zip>45459</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jefferson Neurology Associates-Site Number:8400016</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Premier Neurology-Site Number:8400069</name>
      <address>
        <city>Greer</city>
        <state>South Carolina</state>
        <zip>29650</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advanced Neuroscience Center-Site Number:8400035</name>
      <address>
        <city>Franklin</city>
        <state>Tennessee</state>
        <zip>37064</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sibyl Wray, MD, Neurology, PC-Site Number:8400007</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37922</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mt Olympus Medical Research-Site Number:8400163</name>
      <address>
        <city>Katy</city>
        <state>Texas</state>
        <zip>77450</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Center of San Antonio-Site Number:8400036</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78258</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Institute for Neuroogical Disorders-Sherman-Site Number:8400151</name>
      <address>
        <city>Sherman</city>
        <state>Texas</state>
        <zip>75092</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurological Associates-Site Number:8400097</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wheaton Franciscan Healthcare-Site Number:8400022</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320004</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1023AAB</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320002</name>
      <address>
        <city>Capital Federal</city>
        <state>Buenos Aires</state>
        <zip>1012</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320001</name>
      <address>
        <city>Caba</city>
        <state>Ciudad De Buenos Aires</state>
        <zip>C1061</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320003</name>
      <address>
        <city>Rosario</city>
        <state>Santa Fe</state>
        <zip>2000</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320005</name>
      <address>
        <city>San Miguel de Tucuman</city>
        <zip>T4000AXL</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560005</name>
      <address>
        <city>Brugge</city>
        <zip>B-8000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560004</name>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560002</name>
      <address>
        <city>Mons</city>
        <zip>7000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560001</name>
      <address>
        <city>Pelt</city>
        <zip>3900</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760001</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90610-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760002</name>
      <address>
        <city>Curitiba</city>
        <zip>81210-310</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760007</name>
      <address>
        <city>Sao Paulo</city>
        <zip>01228-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240002</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2C8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240014</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5A5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240005</name>
      <address>
        <city>Greenfield Park</city>
        <state>Quebec</state>
        <zip>J4V 2J2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240006</name>
      <address>
        <city>Gatineau</city>
        <zip>J8Y1W2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240021</name>
      <address>
        <city>Quebec</city>
        <zip>G1W 4R4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520002</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>7650568</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520005</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>833-0024</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520001</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>8380456</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520003</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>8431657</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520006</name>
      <address>
        <city>Concepción</city>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520004</name>
      <address>
        <city>Valdivia</city>
        <zip>5110683</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1910001</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1910002</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1910003</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030002</name>
      <address>
        <city>Brno</city>
        <zip>65691</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030011</name>
      <address>
        <city>Hradec Kralove</city>
        <zip>50005</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030001</name>
      <address>
        <city>Jihlava</city>
        <zip>58633</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030008</name>
      <address>
        <city>Praha 10</city>
        <zip>10034</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030005</name>
      <address>
        <city>Praha 5 - Motol</city>
        <zip>15006</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500019</name>
      <address>
        <city>Besancon</city>
        <zip>25000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500018</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500011</name>
      <address>
        <city>Bron</city>
        <zip>69500</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500005</name>
      <address>
        <city>Clermont Ferrand</city>
        <zip>63003</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500006</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500010</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500002</name>
      <address>
        <city>Nice</city>
        <zip>06002</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500017</name>
      <address>
        <city>Nimes</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500007</name>
      <address>
        <city>Paris</city>
        <zip>75019</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500004</name>
      <address>
        <city>Poissy</city>
        <zip>78300</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500003</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500001</name>
      <address>
        <city>Strasbourg</city>
        <zip>67098</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760005</name>
      <address>
        <city>Bayreuth</city>
        <zip>95445</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760015</name>
      <address>
        <city>Berlin</city>
        <zip>10713</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760014</name>
      <address>
        <city>Berlin</city>
        <zip>12099</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760020</name>
      <address>
        <city>Bochum</city>
        <zip>44791</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760012</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760003</name>
      <address>
        <city>Würzburg</city>
        <zip>97070</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000001</name>
      <address>
        <city>Athens</city>
        <zip>115 28</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000006</name>
      <address>
        <city>Athens</city>
        <zip>11535</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000002</name>
      <address>
        <city>Athens</city>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000007</name>
      <address>
        <city>Athens</city>
        <zip>15125</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000009</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000004</name>
      <address>
        <city>Larissa</city>
        <zip>41110</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000003</name>
      <address>
        <city>Thessaloniki</city>
        <zip>546 36</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480105</name>
      <address>
        <city>Budapest</city>
        <zip>1135</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480102</name>
      <address>
        <city>Budapest</city>
        <zip>1145</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480106</name>
      <address>
        <city>Kaposvár</city>
        <zip>7400</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480103</name>
      <address>
        <city>Tatabánya</city>
        <zip>2800</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560005</name>
      <address>
        <city>Chandigarh</city>
        <zip>160012</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560007</name>
      <address>
        <city>Gurgaon</city>
        <zip>122001</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560008</name>
      <address>
        <city>Gurgaon</city>
        <zip>122002</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560002</name>
      <address>
        <city>New Delhi</city>
        <zip>110060</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560004</name>
      <address>
        <city>Thiruvananthapuram</city>
        <zip>695004</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3760002</name>
      <address>
        <city>Ashkelon</city>
        <zip>78278</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3760003</name>
      <address>
        <city>Haifa</city>
        <zip>31096</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3760006</name>
      <address>
        <city>Rehovot</city>
        <zip>76100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3760004</name>
      <address>
        <city>Safed</city>
        <zip>13100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3760001</name>
      <address>
        <city>Tel HaShomer</city>
        <zip>52621</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4100001</name>
      <address>
        <city>Goyang-si</city>
        <state>Gyeonggi-do</state>
        <zip>10408</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4100003</name>
      <address>
        <city>Seoul</city>
        <state>Seoul-teukbyeolsi</state>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4100006</name>
      <address>
        <city>Seoul</city>
        <state>Seoul-teukbyeolsi</state>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4100002</name>
      <address>
        <city>Seoul</city>
        <state>Seoul-teukbyeolsi</state>
        <zip>06351</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280002</name>
      <address>
        <city>Riga</city>
        <zip>LV-1002</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280003</name>
      <address>
        <city>Riga</city>
        <zip>LV-1005</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280001</name>
      <address>
        <city>Amsterdam</city>
        <zip>1081 GN</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5780002</name>
      <address>
        <city>Namsos</city>
        <zip>7800</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5780001</name>
      <address>
        <city>Oslo</city>
        <zip>0450</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200001</name>
      <address>
        <city>Braga</city>
        <zip>4710-243</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200005</name>
      <address>
        <city>Coimbra</city>
        <zip>3000-075</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200011</name>
      <address>
        <city>Lisboa</city>
        <zip>1162-050</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200006</name>
      <address>
        <city>Lisboa</city>
        <zip>1649-035</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200002</name>
      <address>
        <city>Matosinhos</city>
        <zip>4464-513</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200010</name>
      <address>
        <city>Porto</city>
        <zip>4099-001</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200004</name>
      <address>
        <city>Santa Maria da Feira</city>
        <zip>4520-211</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>San Juan MS Center-Site Number:8400015</name>
      <address>
        <city>Guaynabo</city>
        <zip>00969</zip>
        <country>Puerto Rico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430006</name>
      <address>
        <city>Barnaul</city>
        <zip>656024</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430013</name>
      <address>
        <city>Bryansk</city>
        <zip>241033</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430012</name>
      <address>
        <city>Ekaterinburg</city>
        <zip>620102</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430001</name>
      <address>
        <city>Kazan</city>
        <zip>420021</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430010</name>
      <address>
        <city>Kirov</city>
        <zip>610998</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430007</name>
      <address>
        <city>Moscow</city>
        <zip>117997</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430005</name>
      <address>
        <city>Moscow</city>
        <zip>127015</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430003</name>
      <address>
        <city>Novosibirsk</city>
        <zip>630087</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430014</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>192242</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430002</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>197110</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430011</name>
      <address>
        <city>Saransk</city>
        <zip>430032</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430004</name>
      <address>
        <city>St-Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880001</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880003</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880006</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880002</name>
      <address>
        <city>Kragujevac</city>
        <zip>34000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880004</name>
      <address>
        <city>Nis</city>
        <zip>18000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880005</name>
      <address>
        <city>Novi Sad</city>
        <zip>21000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030001</name>
      <address>
        <city>Bratislava</city>
        <zip>82606</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030002</name>
      <address>
        <city>Martin</city>
        <zip>03659</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030004</name>
      <address>
        <city>Nitra</city>
        <zip>950 01</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240011</name>
      <address>
        <city>Sevilla</city>
        <state>Andalucia</state>
        <zip>41009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240006</name>
      <address>
        <city>Barcelona</city>
        <state>Barcelona [Barcelona]</state>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240009</name>
      <address>
        <city>Barakaldo</city>
        <state>Bizkaia</state>
        <zip>48903</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240004</name>
      <address>
        <city>Salt</city>
        <state>Girona [Gerona]</state>
        <zip>17190</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240013</name>
      <address>
        <city>Las Palmas de Gran Canaria</city>
        <state>Las Palmas</state>
        <zip>35010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240007</name>
      <address>
        <city>Hospitalet de Llobregat</city>
        <zip>08907</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240008</name>
      <address>
        <city>La Coruña</city>
        <zip>15006</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240005</name>
      <address>
        <city>Lleida</city>
        <zip>25198</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240003</name>
      <address>
        <city>Madrid</city>
        <zip>28007</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240001</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240002</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240010</name>
      <address>
        <city>Málaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240012</name>
      <address>
        <city>Pozuelo De Alarcón</city>
        <zip>28223</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7560003</name>
      <address>
        <city>Aarau</city>
        <zip>5001</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7560002</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7560004</name>
      <address>
        <city>Lugano</city>
        <zip>6903</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920002</name>
      <address>
        <city>Ankara</city>
        <zip>06100</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920005</name>
      <address>
        <city>Besevler / Ankara</city>
        <zip>06500</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920006</name>
      <address>
        <city>Istanbul</city>
        <zip>34896</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920004</name>
      <address>
        <city>Kuttahta</city>
        <zip>43100</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920001</name>
      <address>
        <city>Samsun</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920003</name>
      <address>
        <city>Trabzon</city>
        <zip>61080</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040020</name>
      <address>
        <city>Chernihiv</city>
        <zip>14029</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040002</name>
      <address>
        <city>Chernivtsi</city>
        <zip>58000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040019</name>
      <address>
        <city>Chernivtsi</city>
        <zip>58023</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040005</name>
      <address>
        <city>Dnipro</city>
        <zip>49005</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040022</name>
      <address>
        <city>Kharkiv</city>
        <zip>61103</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040018</name>
      <address>
        <city>Kharkiv</city>
        <zip>61166</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040007</name>
      <address>
        <city>Kyiv</city>
        <zip>02091</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040006</name>
      <address>
        <city>Lviv</city>
        <zip>79013</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040003</name>
      <address>
        <city>Vinnytsia</city>
        <zip>21050</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260003</name>
      <address>
        <city>Exeter</city>
        <state>Devon</state>
        <zip>EX2 5DW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260016</name>
      <address>
        <city>Canterbury</city>
        <state>Kent</state>
        <zip>CT1 3NG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260009</name>
      <address>
        <city>Bristol</city>
        <zip>BS10 5NB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Belgium</country>
    <country>Brazil</country>
    <country>Canada</country>
    <country>Chile</country>
    <country>Croatia</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>India</country>
    <country>Israel</country>
    <country>Korea, Republic of</country>
    <country>Latvia</country>
    <country>Netherlands</country>
    <country>Norway</country>
    <country>Portugal</country>
    <country>Puerto Rico</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>Slovakia</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>Turkey</country>
    <country>Ukraine</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>May 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 1, 2020</study_first_posted>
  <last_update_submitted>August 4, 2023</last_update_submitted>
  <last_update_submitted_qc>August 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </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>Teriflunomide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04410991
org study id: EFC16034
secondary id: U1111-1238-1373
nct id: NCT04410991
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Primary Objective:

      To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide
      (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with
      relapsing forms of MS

      Secondary Objective:

      To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability
      progression, MRI lesions, cognitive performance and quality of life To evaluate the safety
      and tolerability of daily SAR442168 To evaluate pharmacodynamics (PD) of SAR442168
Study duration will vary per participant in this event driven trial with a treatment duration
      of approximately 18 to 36 months. Participants completing the study will be offered to
      participate in a long term safety study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses
time frame: Up to approximately 36 months
description: Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses
measure: Time to onset of confirmed disability worsening confirmed over at least 6 months
time frame: Up to approximately 36 months
description: ime to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows:
increase of ≥1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0 OR
increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5 OR
increase of ≥0.5 point from the baseline EDSS score when the baseline score is >5.5 - 5.
measure: Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months
time frame: Up to 36 approximately months
measure: Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study
time frame: From 6 months up to approximately 36 months
measure: Total Number of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the End of study (EOS)
time frame: From 6 months up to approximately 36 months
measure: Change in cognitive function
time frame: From Baseline up to 36 approximately months
description: Change in cognitive function from baseline to the EOS as assessed by the SDMT and CVLT-II where available
measure: Time to confirmed disability improvement
time frame: From Baseline up to approximately 36 months
description: Time to confirmed disability improvement (CDI), defined as a ≥1.0 point decrease on the EDSS from the baseline EDSS score confirmed over at least 6 months
measure: Percent change in Brain volume Loss as detected by brain MRI
time frame: From 6 months up to approximately 36 months
description: Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS
measure: Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54)
time frame: From Baseline up to approximately 36 months
description: Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
measure: Number of participants with adverse events A(Es) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
time frame: From screening until end of study approximately 36 months
measure: Change in plasma neurofilament light chain (NfL)
time frame: From Baseline until end of study up to approximately 36 months -
description: Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baselineC
measure: Changes in plasma Immunoglobulin level
time frame: From Baseline until end of study up to 36 approximately months
description: Changes in serum immunoglobulin level at the EOS compared to baseline
measure: Change in serum chitinase-3 like protein 1 (Chi3L1) -
time frame: From Baseline until end of study up to approximately 36 months -
description: Change in serum Chi3L1 levels at the EOS compared to baseline -
arm group label: SAR442168
arm group type: Experimental
description: Dose 1 of oral SAR442168 daily + placebo to match the teriflunomide tablet once daily
arm group label: Teriflunomide
arm group type: Active Comparator
description: Oral 14 mg oral teriflunomide + placebo to match the SAR442168 tablet once daily
intervention type: Drug
intervention name: Tolebrutinib
description: Pharmaceutical form: Tablet
Route of administration: Oral
arm group label: SAR442168
other name: SAR442168
intervention type: Drug
intervention name: Teriflunomide HMR1726
description: Pharmaceutical form: Tablet
Route of administration: Oral
arm group label: Teriflunomide
intervention type: Drug
intervention name: Placebo to match Tolebrutinib
description: Pharmaceutical form: Tablet
Route of administration: Oral
arm group label: Teriflunomide
intervention type: Drug
intervention name: Placebo to match Teriflunomide
description: Pharmaceutical form: Tablet
Route of administration: Oral
arm group label: SAR442168
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
facility: 
facility: 
facility: 
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country: Argentina
country: Belgium
country: Brazil
country: Canada
country: Chile
country: Croatia
country: Czechia
country: France
country: Germany
country: Greece
country: Hungary
country: India
country: Israel
country: Korea, Republic of
country: Latvia
country: Netherlands
country: Norway
country: Portugal
country: Puerto Rico
country: Russian Federation
country: Serbia
country: Slovakia
country: Spain
country: Switzerland
country: Turkey
country: Ukraine
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Teriflunomide
sharing ipd: Yes
ipd description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org