<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/NCT04411641</url>
  </required_header>
  <id_info>
    <org_study_id>EFC16645</org_study_id>
    <secondary_id>U1111-1246-7768</secondary_id>
    <nct_id>NCT04411641</nct_id>
  </id_info>
  <brief_title>Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168)</brief_title>
  <acronym>HERCULES</acronym>
  <official_title>A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Nonrelapsing Secondary Progressive 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 determine the efficacy of SAR442168 compared to placebo in delaying disability progression&#xD;
      in NRSPMS&#xD;
&#xD;
      Secondary Objective:&#xD;
&#xD;
      To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic&#xD;
      resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of&#xD;
      life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics&#xD;
      (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and&#xD;
      safety 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 24 to 48 months.&#xD;
&#xD;
      Participants completing the treatment period will be proposed to enroll in a separate long&#xD;
      term safety study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 24, 2020</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">August 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>6-month confirmed disability progression (CDP)</measure>
    <time_frame>Up to 48 approximately months</time_frame>
    <description>Time to onset of 6 months CDP defined as follows:&#xD;
-Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.0, or -Increase of ≥0.5 point when the baseline EDSS score is &gt;5.0 -</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>3-months change in T25-FW and 9-HPT</measure>
    <time_frame>Up to approximately 48 months</time_frame>
    <description>Time to onset of composite CDP, confirmed over at least 3 months (3-month CCDP), by the EDSS Plus composite (EDSS score increase, or 20% increase in the T25 FW test, or 20% increase in the 9 hole peg test (9 HPT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month CDP</measure>
    <time_frame>Up to approximately48 months</time_frame>
    <description>Time to onset of 3-month CDP as assessed by EDSS score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New and enlarging T2 hyperintense lesions by MRI</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Total number of new or enlarging T2 hyperintense lesions as detected by MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to onset of confirmed disability improvement (CDI)</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Time to CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain volume loss (BVL)</measure>
    <time_frame>From 6 Months up to approximately 48 months</time_frame>
    <description>Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cognitive function</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54)</measure>
    <time_frame>From Baseline up to approximately 48 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>Safety and Tolerability</measure>
    <time_frame>From Screening until end of study up to approximately 48 months</time_frame>
    <description>Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Population pharmacokinetics</measure>
    <time_frame>Months 6, 9 and 12</time_frame>
    <description>Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in plasma neurofilament light chain (NfL)</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Change in NfL levels at the EOS compared to baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in serum Immunoglobulin level</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Changes in serum Immunoglobulin level at the EOS compared to baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lymphocyte phenotype subsets</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum chitinase-3 like protein 1 (Chi3L1)</measure>
    <time_frame>From Baseline up to approximately 48 months</time_frame>
    <description>Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1131</enrollment>
  <condition>Secondary Progressive 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 once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo tablet to match SAR442168 once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolebrutinib</intervention_name>
    <description>Pharmaceutical form: Film-coated tablet 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>Placebo to match Tolebrutinib</intervention_name>
    <description>Pharmaceutical form: Film-coated tablet Route of administration: Oral</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria :&#xD;
&#xD;
          -  18 to 60 years of age inclusive&#xD;
&#xD;
          -  Diagnosis of nonrelapsing secondary progressive multiple sclerosis according to the&#xD;
             2017 McDonald criteria&#xD;
&#xD;
          -  Expanded disability status scale (EDSS) between 3.0 to 6.5 points inclusive, at&#xD;
             screening&#xD;
&#xD;
          -  The participant must have documented evidence of disability progression observed&#xD;
             during the 12 months before screening&#xD;
&#xD;
          -  Absence of clinical relapses for at least 24 months&#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;
          -  A female participant is eligible to participate if she is not pregnant or&#xD;
             breastfeeding, and at least one of the following conditions applies:&#xD;
&#xD;
          -  Is not a WOCBP OR&#xD;
&#xD;
          -  Is a WOCBP and agrees to use an acceptable contraceptive method&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  The participant has conditions that would adversely affect study participation such as&#xD;
             short life expectancy.&#xD;
&#xD;
          -  History of organ transplant.&#xD;
&#xD;
          -  Evidence of infection with human immuodeficiency virus (HIV), transplantation,&#xD;
             progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or&#xD;
             latent tuberculosis or other active infections that would adversely affect study&#xD;
             participation.&#xD;
&#xD;
          -  Persistent chronic or active or recurring system infection, that may adversely affect&#xD;
             participation or IMP administration in this study, as judged by the Investigator.&#xD;
&#xD;
          -  History of malignancy within 5 years prior to screening.&#xD;
&#xD;
          -  History of alcohol or drug abuse within 1 year prior to screening.&#xD;
&#xD;
          -  Hospitalized for psychiatric disease within 2 years prior to screening.&#xD;
&#xD;
          -  Clinically significant laboratory abnormalities (including evidence of liver injury)&#xD;
             or electrocardiogram abnormalities at screening&#xD;
&#xD;
          -  Bleeding disorder, known platelet dysfunctionat any time prior to the screening visit&#xD;
&#xD;
          -  A platelet count &lt;150 000/μL at the screening visit&#xD;
&#xD;
          -  A history of significant bleeding event within 6 months prior to screening, according&#xD;
             to the Investigator's judgment such as, but not limited to cerebral or&#xD;
             gastrointestinal bleeding.&#xD;
&#xD;
          -  Lymphocyte count below the lower limit of normal at screening.&#xD;
&#xD;
          -  Recent live (attenuated) vaccine within 2 months before the first treatment visit.&#xD;
&#xD;
          -  Recent major surgery (within 4 weeks of screening) or planned major surgery during the&#xD;
             study.&#xD;
&#xD;
          -  The participant has received medications/treatments for MS within a specified time&#xD;
             frame.&#xD;
&#xD;
          -  Receiving potent and moderate inducers or inhibitors of cytochrome P450 3A (CYP3A) or&#xD;
             potent inhibitors of CYP2C8 hepatic enzymes.&#xD;
&#xD;
          -  Receiving anticoagulant or antiplatelet therapy (such as aspirin&gt;81mg/day,&#xD;
             clopidogrel, warfarin).&#xD;
&#xD;
          -  Contraindications to magnetic resonance imaging (MRI).&#xD;
&#xD;
        The above information is not intended to contain all considerations relevant to a patient's&#xD;
        potential participation in a clinical trial.&#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>Clinical Sciences &amp; Operations</last_name>
    <role>Study Director</role>
    <affiliation>Sanofi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama MS Center-Site Number:8400013</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</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>UC San Diego ACTRI-Site Number:8400101</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Collaborative Neuroscience Research-Site Number:8400045</name>
      <address>
        <city>Long Beach</city>
        <state>California</state>
        <zip>90806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Multiple Sclerosis Center-Site Number:8400143</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of San Francisco, Sandler Neurosciences Center-Site Number:8400137</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</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>Regina Berkovich, MD, PhD-Site Number:8400059</name>
      <address>
        <city>West Hollywood</city>
        <state>California</state>
        <zip>90048</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>University of Colorado-Site Number:8400012</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80262</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>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>Aqualane Clinical Research-Site Number:8400027</name>
      <address>
        <city>Naples</city>
        <state>Florida</state>
        <zip>34105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Axiom Clinical Research of Florida-Site Number:8400001</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33609-4052</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>University of Kansas Medical Center-Site Number:8400023</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160-7321</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>Tufts Medical Center-Site Number:8400072</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Massachusetts-Site Number:8400014</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</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>The Memorial Hospital-Site Number:8400033</name>
      <address>
        <city>Owosso</city>
        <state>Michigan</state>
        <zip>48867</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>Mayo Clinic-Site Number:8400111</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Missouri Baptist Medical Center-Site Number:8400019</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63131</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lou Ruvo Center for Brain Health-Site Number:8400117</name>
      <address>
        <city>Las Vegas</city>
        <state>Nevada</state>
        <zip>89106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Holy Name Hospital-Site Number:8400104</name>
      <address>
        <city>Teaneck</city>
        <state>New Jersey</state>
        <zip>07666</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>Icahn School of Medicine at Mount Sinai (Department of Endoc-Site Number:8400038</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029-6501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Associates of Stony Brook-Site Number:8400042</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794</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>University Hospitals CMC-Site Number:8400083</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic-Site Number:8400125</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Optimed Research, LTD-Site Number:8400147</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43235</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Specialists-Site Number:8400002</name>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <zip>45417</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbus Neuroscience-Site Number:8400010</name>
      <address>
        <city>Westerville</city>
        <state>Ohio</state>
        <zip>40382</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Providence Multiple Sclerosis Center-Site Number:8400020</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97225</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Perelman Center for Advanced Medicine-Site Number:8400142</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</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>Mountain View Clinical Research-Site Number:8400024</name>
      <address>
        <city>Greer</city>
        <state>South Carolina</state>
        <zip>29651-1817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Clinic, PC-Site Number:8400087</name>
      <address>
        <city>Cordova</city>
        <state>Tennessee</state>
        <zip>38018</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>Baylor College of Medicine-Site Number:8400136</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</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>University Of Vermont College Of Medicine-Site Number:8400130</name>
      <address>
        <city>Burlington</city>
        <state>Vermont</state>
        <zip>05401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin-Site Number:8400028</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</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 :0320007</name>
      <address>
        <city>Buenos Aires</city>
        <zip>1860</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320006</name>
      <address>
        <city>Córdoba</city>
        <zip>5000</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 :0360003</name>
      <address>
        <city>Woolloongabba</city>
        <state>Queensland</state>
        <zip>4102</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360002</name>
      <address>
        <city>Kent Town</city>
        <state>South Australia</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360004</name>
      <address>
        <city>Hobart</city>
        <state>Tasmania</state>
        <zip>7001</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360001</name>
      <address>
        <city>Fitzroy</city>
        <state>Victoria</state>
        <zip>3065</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360006</name>
      <address>
        <city>Heidelberg West</city>
        <state>Victoria</state>
        <zip>3081</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0400003</name>
      <address>
        <city>Innsbruck</city>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0400001</name>
      <address>
        <city>Linz</city>
        <zip>4020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0400004</name>
      <address>
        <city>Linz</city>
        <zip>4021</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0400002</name>
      <address>
        <city>Wien</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1120004</name>
      <address>
        <city>Vitebsk</city>
        <zip>210009</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1120005</name>
      <address>
        <city>Vitebsk</city>
        <zip>210037</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560007</name>
      <address>
        <city>Bruxelles</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560003</name>
      <address>
        <city>Edegem</city>
        <zip>B-2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560006</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560008</name>
      <address>
        <city>Liège</city>
        <zip>4000</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 :1000002</name>
      <address>
        <city>Pleven</city>
        <zip>5800</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1000005</name>
      <address>
        <city>Plovdiv</city>
        <zip>4000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1000004</name>
      <address>
        <city>Sofia</city>
        <zip>1113</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1000008</name>
      <address>
        <city>Sofia</city>
        <zip>1407</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1000001</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1000006</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1000009</name>
      <address>
        <city>Sofia</city>
        <zip>1680</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240017</name>
      <address>
        <city>Burnaby</city>
        <state>British Columbia</state>
        <zip>V5G 2X6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240011</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H 1V7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240003</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240008</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240006</name>
      <address>
        <city>Gatineau</city>
        <state>Quebec</state>
        <zip>J8Y 1W2</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 :1240004</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2X 0A9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240015</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3A 2B4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240007</name>
      <address>
        <city>Sherbrooke</city>
        <state>Quebec</state>
        <zip>J1H 5N4</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 :1560006</name>
      <address>
        <city>Beijing</city>
        <zip>100034</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560012</name>
      <address>
        <city>Beijing</city>
        <zip>100053</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560021</name>
      <address>
        <city>Beijing</city>
        <zip>100700</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560003</name>
      <address>
        <city>Beijing</city>
        <zip>100730</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560009</name>
      <address>
        <city>Beijing</city>
        <zip>100730</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560004</name>
      <address>
        <city>Changchun</city>
        <zip>130021</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560015</name>
      <address>
        <city>Changsha</city>
        <zip>410008</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560005</name>
      <address>
        <city>Chengdu</city>
        <zip>610041</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560019</name>
      <address>
        <city>Chongqing</city>
        <zip>400016</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560035</name>
      <address>
        <city>Fuzhou</city>
        <zip>350005</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560001</name>
      <address>
        <city>Guangzhou</city>
        <zip>510630</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560007</name>
      <address>
        <city>Hangzhou</city>
        <zip>310009</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560014</name>
      <address>
        <city>Shijiazhuang</city>
        <zip>050000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560008</name>
      <address>
        <city>Taiyuan</city>
        <zip>030001</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1560017</name>
      <address>
        <city>Xi'an</city>
        <zip>710038</zip>
        <country>China</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 :2030004</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 :2030010</name>
      <address>
        <city>Ostrava - Poruba</city>
        <zip>70852</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030005</name>
      <address>
        <city>Praha 2</city>
        <zip>12808</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030003</name>
      <address>
        <city>Teplice</city>
        <zip>415 29</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2080001</name>
      <address>
        <city>Esbjerg</city>
        <zip>6700</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2080005</name>
      <address>
        <city>Holstebro</city>
        <zip>7500</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2080004</name>
      <address>
        <city>Odense</city>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2460003</name>
      <address>
        <city>Helsinki</city>
        <zip>00180</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2460001</name>
      <address>
        <city>Tampere</city>
        <zip>33520</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2460002</name>
      <address>
        <city>Turku</city>
        <zip>20520</zip>
        <country>Finland</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 :2500015</name>
      <address>
        <city>Gonesse</city>
        <zip>95500</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500009</name>
      <address>
        <city>Lille</city>
        <zip>59037</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 :2500008</name>
      <address>
        <city>Nancy</city>
        <zip>54035</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 :2500017</name>
      <address>
        <city>Nimes</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500016</name>
      <address>
        <city>Paris</city>
        <zip>75012</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500014</name>
      <address>
        <city>Paris</city>
        <zip>75013</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 :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 :2500012</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</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 :2760009</name>
      <address>
        <city>Berlin</city>
        <zip>10117</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760001</name>
      <address>
        <city>Dresden</city>
        <zip>01307</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 :2760002</name>
      <address>
        <city>Gießen</city>
        <zip>35385</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760010</name>
      <address>
        <city>Halle (Saale)</city>
        <zip>06120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760006</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760008</name>
      <address>
        <city>Münster</city>
        <zip>48149</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760004</name>
      <address>
        <city>Rostock</city>
        <zip>18055</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760011</name>
      <address>
        <city>Ulm</city>
        <zip>89081</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 :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 :3000005</name>
      <address>
        <city>Thessaloniki</city>
        <zip>57010</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480008</name>
      <address>
        <city>Budapest</city>
        <zip>1135</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480004</name>
      <address>
        <city>Budapest</city>
        <zip>1145</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480007</name>
      <address>
        <city>Budapest</city>
        <zip>1152</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480002</name>
      <address>
        <city>Pécs</city>
        <zip>7623</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480001</name>
      <address>
        <city>Szeged</city>
        <zip>6725</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480006</name>
      <address>
        <city>Tatabánya</city>
        <zip>2800</zip>
        <country>Hungary</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 :3560003</name>
      <address>
        <city>Gurgaon</city>
        <zip>122002</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560005</name>
      <address>
        <city>India</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560004</name>
      <address>
        <city>Mangaluru</city>
        <zip>575018</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3560006</name>
      <address>
        <city>New Delhi</city>
        <zip>110029</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 :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 :3760008</name>
      <address>
        <city>Jerusalem</city>
        <zip>91120</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 :3760004</name>
      <address>
        <city>Zefat</city>
        <zip>13100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800011</name>
      <address>
        <city>Bergamo</city>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800007</name>
      <address>
        <city>Cagliari</city>
        <zip>09126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800012</name>
      <address>
        <city>Firenze</city>
        <zip>50134</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800016</name>
      <address>
        <city>Firenze</city>
        <zip>50141</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800014</name>
      <address>
        <city>Genova</city>
        <zip>16132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800013</name>
      <address>
        <city>L'Aquila</city>
        <zip>67010</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800004</name>
      <address>
        <city>Milano</city>
        <zip>20122</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800001</name>
      <address>
        <city>Milano</city>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800010</name>
      <address>
        <city>Milano</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800008</name>
      <address>
        <city>Pavia</city>
        <zip>27100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800005</name>
      <address>
        <city>Roma</city>
        <zip>00152</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3800009</name>
      <address>
        <city>Roma</city>
        <zip>00168</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920016</name>
      <address>
        <city>Chiba-shi</city>
        <state>Chiba</state>
        <zip>260-8677</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920022</name>
      <address>
        <city>Morioka-shi</city>
        <state>Iwate</state>
        <zip>020-8505</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920011</name>
      <address>
        <city>Kyoto-shi</city>
        <state>Kyoto</state>
        <zip>616-8255</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920020</name>
      <address>
        <city>Sendai-shi</city>
        <state>Miyagi</state>
        <zip>980-8574</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920005</name>
      <address>
        <city>Niigata-shi</city>
        <state>Niigata</state>
        <zip>951-8520</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920004</name>
      <address>
        <city>Moriguchi-shi</city>
        <state>Osaka</state>
        <zip>570-8507</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920001</name>
      <address>
        <city>Osaka-shi</city>
        <state>Osaka</state>
        <zip>556-0016</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920018</name>
      <address>
        <city>Kawagoe-shi</city>
        <state>Saitama</state>
        <zip>350-8550</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920003</name>
      <address>
        <city>Kodaira-shi</city>
        <state>Tokyo</state>
        <zip>187-8551</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920010</name>
      <address>
        <city>Ota-ku</city>
        <state>Tokyo</state>
        <zip>146-0065</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920009</name>
      <address>
        <city>Ube-shi</city>
        <state>Yamaguchi</state>
        <zip>755-8505</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3920023</name>
      <address>
        <city>Sagamihara-shi</city>
        <zip>252-0392</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400003</name>
      <address>
        <city>Kaunas</city>
        <zip>50161</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400002</name>
      <address>
        <city>Klaipeda</city>
        <zip>92288</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400001</name>
      <address>
        <city>Vilnius</city>
        <zip>08661</zip>
        <country>Lithuania</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 :5280003</name>
      <address>
        <city>Breda</city>
        <zip>4818 CK</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280006</name>
      <address>
        <city>Groningen</city>
        <zip>9728 NZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280002</name>
      <address>
        <city>Sittard-Geleen</city>
        <zip>6162 BG</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5780003</name>
      <address>
        <city>Bergen</city>
        <zip>5021</zip>
        <country>Norway</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 :6160003</name>
      <address>
        <city>Bydgoszcz</city>
        <state>Kujawsko-pomorskie</state>
        <zip>85-796</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160005</name>
      <address>
        <city>Warszawa</city>
        <state>Mazowieckie</state>
        <zip>01-211</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160006</name>
      <address>
        <city>Warszawa</city>
        <state>Mazowieckie</state>
        <zip>01-684</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160002</name>
      <address>
        <city>Katowice</city>
        <state>Slaskie</state>
        <zip>40-571</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160007</name>
      <address>
        <city>Katowice</city>
        <state>Slaskie</state>
        <zip>40-684</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160004</name>
      <address>
        <city>Katowice</city>
        <state>Slaskie</state>
        <zip>40-686</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160008</name>
      <address>
        <city>Plewiska</city>
        <state>Wielkopolskie</state>
        <zip>62-064</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160001</name>
      <address>
        <city>Lodz</city>
        <zip>90-549</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160012</name>
      <address>
        <city>Lublin</city>
        <zip>20-016</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160011</name>
      <address>
        <city>Zabrze</city>
        <zip>41-800</zip>
        <country>Poland</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 :6200011</name>
      <address>
        <city>Lisboa</city>
        <zip>1162-050</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200007</name>
      <address>
        <city>Lisboa</city>
        <zip>1349-019</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 :6420008</name>
      <address>
        <city>Bucuresti</city>
        <zip>022328</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420004</name>
      <address>
        <city>Campulung</city>
        <zip>115100</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420006</name>
      <address>
        <city>Cluj-Napoca</city>
        <zip>400012</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420003</name>
      <address>
        <city>Constanta</city>
        <zip>900123</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420013</name>
      <address>
        <city>Oradea</city>
        <zip>410154</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420005</name>
      <address>
        <city>Sibiu</city>
        <zip>550052</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420001</name>
      <address>
        <city>Targu Mures</city>
        <zip>540136</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6420002</name>
      <address>
        <city>Timisoara</city>
        <zip>300736</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430018</name>
      <address>
        <city>Barnaul</city>
        <zip>656024</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430023</name>
      <address>
        <city>Ekaterinburg</city>
        <zip>620102</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430025</name>
      <address>
        <city>Kaliningrad</city>
        <zip>236035</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430003</name>
      <address>
        <city>Kazan</city>
        <zip>420021</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430022</name>
      <address>
        <city>Kemerovo</city>
        <zip>650099</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430017</name>
      <address>
        <city>Kirov</city>
        <zip>610998</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430024</name>
      <address>
        <city>Krasnoyarsk</city>
        <zip>660029</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430020</name>
      <address>
        <city>Moscow</city>
        <zip>117997</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430002</name>
      <address>
        <city>Moscow</city>
        <zip>125367</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430013</name>
      <address>
        <city>Moscow</city>
        <zip>127015</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430001</name>
      <address>
        <city>Moscow</city>
        <zip>129110</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430008</name>
      <address>
        <city>Moscow</city>
        <zip>129128</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430021</name>
      <address>
        <city>Nizhny Novgorod</city>
        <zip>603137</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430006</name>
      <address>
        <city>Nizhny Novgorod</city>
        <zip>603155</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430005</name>
      <address>
        <city>Novosibirsk</city>
        <zip>630087</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430026</name>
      <address>
        <city>Perm</city>
        <zip>614990</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430007</name>
      <address>
        <city>Pyatigorsk</city>
        <zip>357538</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430016</name>
      <address>
        <city>Rostov-on-Don</city>
        <zip>344022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430004</name>
      <address>
        <city>Saint-Petersburg</city>
        <zip>197110</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430009</name>
      <address>
        <city>Samara</city>
        <zip>443095</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430019</name>
      <address>
        <city>Saransk</city>
        <zip>430032</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430014</name>
      <address>
        <city>Smolensk</city>
        <zip>214018</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430011</name>
      <address>
        <city>St-Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430012</name>
      <address>
        <city>Tyumen</city>
        <zip>625000</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430010</name>
      <address>
        <city>Ufa</city>
        <zip>450005</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240007</name>
      <address>
        <city>Sevilla</city>
        <state>Andalucia</state>
        <zip>41009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240013</name>
      <address>
        <city>Barcelona</city>
        <state>Barcelona [Barcelona]</state>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240016</name>
      <address>
        <city>Barcelona</city>
        <state>Barcelona [Barcelona]</state>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240014</name>
      <address>
        <city>Salt</city>
        <state>Girona [Gerona]</state>
        <zip>17190</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240017</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 :7240004</name>
      <address>
        <city>Majadahonda</city>
        <state>Madrid</state>
        <zip>28222</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240001</name>
      <address>
        <city>Pozuelo De Alarcón</city>
        <state>Madrid</state>
        <zip>28223</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240012</name>
      <address>
        <city>Donostia</city>
        <state>Pais Vasco</state>
        <zip>20014</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240008</name>
      <address>
        <city>Córdoba</city>
        <zip>14004</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240015</name>
      <address>
        <city>Lleida</city>
        <zip>25198</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240005</name>
      <address>
        <city>Madrid</city>
        <zip>28007</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240002</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240003</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240010</name>
      <address>
        <city>Murcia</city>
        <zip>30120</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240009</name>
      <address>
        <city>Málaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240011</name>
      <address>
        <city>Valencia</city>
        <zip>46026</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920005</name>
      <address>
        <city>Eskisehir</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920010</name>
      <address>
        <city>Hatay</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920002</name>
      <address>
        <city>Istanbul</city>
        <zip>34098</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920009</name>
      <address>
        <city>Istanbul</city>
        <zip>34688</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920007</name>
      <address>
        <city>Istanbul</city>
        <zip>34785</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 :7920003</name>
      <address>
        <city>Istanbul</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920013</name>
      <address>
        <city>Izmir</city>
        <zip>35100</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920001</name>
      <address>
        <city>Izmit</city>
        <zip>41380</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920011</name>
      <address>
        <city>Kütahya</city>
        <zip>43100</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920012</name>
      <address>
        <city>Mersin</city>
        <zip>33070</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7920008</name>
      <address>
        <city>Trabzon</city>
        <zip>61080</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040008</name>
      <address>
        <city>Chernivtsi</city>
        <zip>58000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040016</name>
      <address>
        <city>Chernivtsi</city>
        <zip>58023</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040003</name>
      <address>
        <city>Dnipro</city>
        <zip>49005</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040010</name>
      <address>
        <city>Ivano-Frankivsk</city>
        <zip>76018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040007</name>
      <address>
        <city>Kharkiv</city>
        <zip>61068</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040011</name>
      <address>
        <city>Kharkiv</city>
        <zip>61103</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040012</name>
      <address>
        <city>Kharkiv</city>
        <zip>61103</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040013</name>
      <address>
        <city>Kyiv</city>
        <zip>03115</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040005</name>
      <address>
        <city>Lutsk</city>
        <zip>43005</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040009</name>
      <address>
        <city>Lviv</city>
        <zip>79010</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040004</name>
      <address>
        <city>Lviv</city>
        <zip>79013</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040002</name>
      <address>
        <city>Odesa</city>
        <zip>65025</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040006</name>
      <address>
        <city>Vinnytsia</city>
        <zip>21050</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040014</name>
      <address>
        <city>Zhytomyr</city>
        <zip>10002</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 :8260008</name>
      <address>
        <city>Plymouth</city>
        <state>Devon</state>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260010</name>
      <address>
        <city>Swansea</city>
        <state>Neath Port Talbot</state>
        <zip>SA6 6NL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260012</name>
      <address>
        <city>Nottingham</city>
        <state>Nottinghamshire</state>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260013</name>
      <address>
        <city>Oxford</city>
        <state>Oxfordshire</state>
        <zip>OX3 9DZ</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>
    <facility>
      <name>Investigational Site Number :8260001</name>
      <address>
        <city>Cardiff</city>
        <zip>CF4 4XY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260005</name>
      <address>
        <city>London</city>
        <zip>SW17 0RE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260018</name>
      <address>
        <city>London</city>
        <zip>W6 8RF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260014</name>
      <address>
        <city>Newcastle Upon Tyne</city>
        <zip>NE1 4LP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260019</name>
      <address>
        <city>Salford</city>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belarus</country>
    <country>Belgium</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>China</country>
    <country>Czechia</country>
    <country>Denmark</country>
    <country>Finland</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>India</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Lithuania</country>
    <country>Netherlands</country>
    <country>Norway</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Romania</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Turkey</country>
    <country>Ukraine</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>February 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 2, 2020</study_first_posted>
  <last_update_submitted>February 9, 2023</last_update_submitted>
  <last_update_submitted_qc>February 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 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>Neoplasm Metastasis</mesh_term>
    <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>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/NCT04411641
org study id: EFC16645
secondary id: U1111-1246-7768
nct id: NCT04411641
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Primary Objective:

      To determine the efficacy of SAR442168 compared to placebo in delaying disability progression
      in NRSPMS

      Secondary Objective:

      To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic
      resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of
      life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics
      (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and
      safety To evaluate pharmacodynamics (PD) of SAR442168
Study duration will vary per participant in this event driven trial with a treatment duration
      of approximately 24 to 48 months.

      Participants completing the treatment period will be proposed to enroll in a separate long
      term safety study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: 6-month confirmed disability progression (CDP)
time frame: Up to 48 approximately months
description: Time to onset of 6 months CDP defined as follows:
-Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.0, or -Increase of ≥0.5 point when the baseline EDSS score is >5.0 -
measure: 3-months change in T25-FW and 9-HPT
time frame: Up to approximately 48 months
description: Time to onset of composite CDP, confirmed over at least 3 months (3-month CCDP), by the EDSS Plus composite (EDSS score increase, or 20% increase in the T25 FW test, or 20% increase in the 9 hole peg test (9 HPT)
measure: 3-month CDP
time frame: Up to approximately48 months
description: Time to onset of 3-month CDP as assessed by EDSS score
measure: New and enlarging T2 hyperintense lesions by MRI
time frame: From Baseline up to approximately 48 months
description: Total number of new or enlarging T2 hyperintense lesions as detected by MRI
measure: Time to onset of confirmed disability improvement (CDI)
time frame: From Baseline up to approximately 48 months
description: Time to CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months
measure: Brain volume loss (BVL)
time frame: From 6 Months up to approximately 48 months
description: Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6
measure: Change in cognitive function
time frame: From Baseline up to approximately 48 months
description: Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II)
measure: Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54)
time frame: From Baseline up to approximately 48 months
description: Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
measure: Safety and Tolerability
time frame: From Screening until end of study up to approximately 48 months
description: Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
measure: Population pharmacokinetics
time frame: Months 6, 9 and 12
description: Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12
measure: Change in plasma neurofilament light chain (NfL)
time frame: From Baseline up to approximately 48 months
description: Change in NfL levels at the EOS compared to baseline
measure: Changes in serum Immunoglobulin level
time frame: From Baseline up to approximately 48 months
description: Changes in serum Immunoglobulin level at the EOS compared to baseline
measure: Change in lymphocyte phenotype subsets
time frame: From Baseline up to approximately 48 months
description: Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants
measure: Change in serum chitinase-3 like protein 1 (Chi3L1)
time frame: From Baseline up to approximately 48 months
description: Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline
arm group label: SAR442168
arm group type: Experimental
description: Dose 1 of oral SAR442168 once daily
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo tablet to match SAR442168 once daily
intervention type: Drug
intervention name: Tolebrutinib
description: Pharmaceutical form: Film-coated tablet Route of administration: Oral
arm group label: SAR442168
other name: SAR442168
intervention type: Drug
intervention name: Placebo to match Tolebrutinib
description: Pharmaceutical form: Film-coated tablet Route of administration: Oral
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
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country: Argentina
country: Australia
country: Austria
country: Belarus
country: Belgium
country: Bulgaria
country: Canada
country: China
country: Czechia
country: Denmark
country: Finland
country: France
country: Germany
country: Greece
country: Hungary
country: India
country: Israel
country: Italy
country: Japan
country: Lithuania
country: Netherlands
country: Norway
country: Poland
country: Portugal
country: Romania
country: Russian Federation
country: Spain
country: Turkey
country: Ukraine
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Chronic Progressive
mesh term: Sclerosis
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