<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/NCT03232073</url>
  </required_header>
  <id_info>
    <org_study_id>AC-058B303</org_study_id>
    <secondary_id>2016-004719-10</secondary_id>
    <nct_id>NCT03232073</nct_id>
  </id_info>
  <brief_title>Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis</brief_title>
  <acronym>OPTIMUM-LT</acronym>
  <official_title>Multicenter, Non-comparative Extension of Study AC-058B301, to Investigate the Long-term Safety, Tolerability, and Control of Disease of Ponesimod 20 mg in Subjects With Relapsing Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Actelion</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Actelion</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study AC-058B301 (OPTIMUM; NCT02425644) has been designed to investigate the efficacy,&#xD;
      safety and tolerability of ponesimod in subjects with relapsing multiple sclerosis (RMS). The&#xD;
      AC-058B303 study is the long-term extension for the core study AC-058B301. The purpose of&#xD;
      this long term extension of the core study AC-058B301 is to characterize the long-term&#xD;
      safety, tolerability, and control of disease of ponesimod 20 mg in subjects with RMS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The AC-058B303 study (extension study) is the long-term extension for the AC-058B301 study&#xD;
      (core study). The core study has been designed to investigate the efficacy, safety and&#xD;
      tolerability of ponesimod in subjects with RMS. The subjects are treated with either&#xD;
      ponesimod or the active comparator, teriflunomide in the core study. The purpose of this long&#xD;
      term extension of the core study is to characterize the long-term safety and control of&#xD;
      disease of ponesimod in subjects with RMS. In particular, the study will allow to observe&#xD;
      potential adverse events which may only occur after long term treatment with ponesimod. The&#xD;
      study will also investigate the effect of re-initiation of ponesimod after a brief&#xD;
      interruption in a relatively large population (all subjects treated with ponesimod in the&#xD;
      core study and eligible for the extension study) on disease activity in terms of relapses and&#xD;
      MS-related MRI lesions. There is currently limited guidance on when a new MS treatment should&#xD;
      be started after discontinuation of teriflunomide and the study will contribute with data on&#xD;
      safety and efficacy of switching from teriflunomide to ponesimod after an interruption as&#xD;
      mandated by the protocol. The study will also allow confirmation of sustained efficacy of&#xD;
      ponesimod in terms of relapses, MRI lesions and reduction of disability accumulation during&#xD;
      long-term treatment. In addition, combined data from the core study together with the results&#xD;
      of the current extension study will allow comparison of MS activity in subjects who were&#xD;
      switched from teriflunomide to ponesimod versus those who were treated with ponesimod in both&#xD;
      studies. A vaccination sub-study will be conducted in a sub-set of up to 50 eligible study&#xD;
      participants from selected countries who consent to be vaccinated with the Janssen&#xD;
      coronavirus disease-2019 (COVID-19) vaccine (Ad26.COV2.S) to investigate the immune response&#xD;
      induced by the Janssen COVID-19 vaccine.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 5, 2017</start_date>
  <completion_date type="Anticipated">January 18, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 18, 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is a single-group open-label extension study to investigate long-term safety, tolerability and control of disease of ponesimod 20 mg in subjects with RMS. Statistical analyses will be descriptive and therefore all endpoints are exploratory in nature. All exploratory endpoints are listed under primary outcomes.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annualized confirmed relapse rate (ARR)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>defined as the number of confirmed relapses per subject-year</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time from core study randomization to first confirmed relapse</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Time from enrollment in core study to first confirmed relapse</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to first 12-week confirmed disability accumulation (CDA)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Time from core baseline to first 12-week CDA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to first 24-week confirmed disability accumulation (CDA)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Time from core baseline to first 24-week CDA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Patients with absence of relapses</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Number of patients with absence of relapses during study period</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline in Expanded Disability Status Scale (EDSS)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Change from baseline in EDSS at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of no evidence of disease activity (NEDA) status at end-of-study (EOS) according to NEDA 3</measure>
    <time_frame>Up to 354 weeks</time_frame>
    <description>NEDA 3 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of no evidence of disease activity (NEDA) status at EOS according to NEDA 4</measure>
    <time_frame>Up to 354 weeks</time_frame>
    <description>NEDA 4 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA, and annual brain volume change ≥ -0.4% from baseline to all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent change from baseline in brain volume (PCBV) measured by magnetic resonance imaging (MRI)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Change from baseline in brain volume at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cumulative number of combined unique active lesions (CUAL) measured by MRI</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Cumulative number of combined unique active lesions (CUAL) defined as new Gd+ T1 lesions plus new or enlarging T2 lesions (without double-counting the lesions) at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Determination of number of Gd+ T1 lesions by MRI</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Number of Gd+ T1 lesions at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cumulative number of new or enlarging T2 lesions measured by MRI</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Cumulative number of new or enlarging T2 lesions (relative to baseline) at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of volume of brain lesions measured by MRI</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Determination of MRI lesions (T2 lesions, T1 hypointense lesions) at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Absence of MRI lesions</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Determination of proportion of Gd+ lesions at baseline evolving to persistent black holes (PBHs)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Proportion of Gd+ lesions at baseline evolving to PBHs at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Estimation of incidence rates of adverse events (AEs)</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Incidence rates of treatment-emergent AEs, severe AEs, AEs of special interest and AEs leading to premature discontinuation of study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Estimation of incidence rates of treatment-emergent morphological ECG abnormalities</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>ECG abnormalities as defined by the ECG provider</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of cardiac rhythms measured by electrocardiogram (ECG) parameters</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Absolute values by visit for 12-lead ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline values by visit for cardiac rhythms</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Change from baseline values by visit for ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in ECG parameters from pre-dose to selected post-dose assessments</measure>
    <time_frame>Analysis period: From day 1 in extension study to end-of-treatment (EOT) in extension study, i.e. for up to 240 weeks</time_frame>
    <description>Change in ECG parameters (HR, PR, QRS, QT, QTcB, QTcF) from pre-dose to selected post-dose assessments (1h, 2h, 3h, 4h) on day 1 of extension study and on day of re-initiation of study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Absolute values and percent change from baseline in forced expiratory volume and forced vital capacity</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Absolute values and percent change from baseline in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at all assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of treatment-emergent decrease from baseline in forced expiratory volume and forced vital capacity</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Determination of treatment-emergent decrease from baseline in FEV1 and FVC (absolute and % of predicted)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Absolute change from baseline to end-of-study (EOS) versus change from baseline to end-of-treatment (EOT) in forced expiratory volume and forced vital capacity</measure>
    <time_frame>Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks</time_frame>
    <description>Absolute change from baseline to end-of-study (EOS) versus change from baseline to end-of-treatment (EOT) in FEV1 and FVC (absolute and % of predicted)</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">877</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Ponesimod</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>20 mg administered orally once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ponesimod</intervention_name>
    <description>Ponesimod; Film-coated tablet; Oral use. From Day 1 to Day 14, ponesimod is gradually up-titrated until a maintenance dose of 20 mg is reached from Day 15</description>
    <arm_group_label>Ponesimod</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed informed consent&#xD;
&#xD;
          2. Subjects with MS having completed the double-blind treatment in the core study as&#xD;
             scheduled&#xD;
&#xD;
          3. Compliance with teriflunomide elimination procedure&#xD;
&#xD;
          4. Women of childbearing potential (WOCBP) must have a negative pre-treatment urine&#xD;
             pregnancy test, must agree to undertake 4-weekly urine pregnancy tests, and must have&#xD;
             been using reliable methods of contraception. Fertile male subjects participating in&#xD;
             the study must agree to use a condom.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any of the following cardiovascular conditions on Day 1 pre-dose:&#xD;
&#xD;
               1. Resting heart rate (HR) &lt; 50 bpm;&#xD;
&#xD;
               2. Presence of second degree atrioventricular (AV) block or third degree AV block or&#xD;
                  a QTcF interval &gt; 470 ms (females), &gt; 450 ms (males);&#xD;
&#xD;
          2. Any of the following alerts from central laboratory at Visit 14 of the core study&#xD;
             (EOT) which was confirmed as an alert at repeated testing or not repeated prior to FU1&#xD;
             of the core study:&#xD;
&#xD;
               1. Lymphocyte count: &lt; 0.2 x 109/L;&#xD;
&#xD;
               2. Neutrophil count &lt;1.0 × 109/L;&#xD;
&#xD;
               3. Platelet count &lt; 50 × 109/L;&#xD;
&#xD;
               4. Creatinine clearance &lt; 30 mL/min&#xD;
&#xD;
          3. At Visit 14 of the core study (EOT) &gt;30% decrease from core study baseline FEV1 and/or&#xD;
             FVC;&#xD;
&#xD;
          4. Clinically significant, persistent respiratory AEs (e.g., dyspnea) not resolved prior&#xD;
             to first dosing in the extension study.&#xD;
&#xD;
          5. Macular edema at any time between Visit 1 (Screening) in the core study and Day 1 of&#xD;
             the extension study.&#xD;
&#xD;
          6. Presence of the following at core study Visit 14 (EOT, Week 108), FU1, or abbreviated&#xD;
             visit FU2, or on Day 1 of the extension study pre-dose:&#xD;
&#xD;
               1. Suspected opportunistic infection of the CNS or any other infection which, in the&#xD;
                  opinion of the investigator, contraindicates re-start of the study drug;&#xD;
&#xD;
               2. Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reaction with&#xD;
                  eosinophilia and systemic symptoms.&#xD;
&#xD;
          7. Need for and intention to administer forbidden study treatment-concomitant therapy&#xD;
&#xD;
          8. Women who are pregnant or lactating.&#xD;
&#xD;
          9. Male subjects wishing to parent a child;&#xD;
&#xD;
         10. Treatment with any MS Disease Modifying Therapies;&#xD;
&#xD;
         11. Any other clinically relevant medical or surgical condition, which, in the opinion of&#xD;
             the investigator, would put the subject at risk by participating in the study;&#xD;
&#xD;
         12. Subjects unlikely to comply with the extension study protocol based on investigator&#xD;
             best judgment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tatiana Sidorenko, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Actelion</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Research Center of Southern California, LLC</name>
      <address>
        <city>Carlsbad</city>
        <state>California</state>
        <zip>92011</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Neurology Group</name>
      <address>
        <city>Pomona</city>
        <state>California</state>
        <zip>91767</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mountain View Clinical Research</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Associates of Ormond Beach</name>
      <address>
        <city>Ormond Beach</city>
        <state>Florida</state>
        <zip>32174</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Josephson Wallack Munshower Neurology, PC</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46256</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Raleigh Neurology Associates</name>
      <address>
        <city>Raleigh</city>
        <state>North Carolina</state>
        <zip>27607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio Health</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43214</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Advanced Neurosciences Institute</name>
      <address>
        <city>Franklin</city>
        <state>Tennessee</state>
        <zip>37064</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Grodno University Hospital</name>
      <address>
        <city>Grodno</city>
        <zip>230017</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Minsk City Clinical Hospital 5</name>
      <address>
        <city>Minsk</city>
        <zip>220026</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Republican Scientific Clinical Centre</name>
      <address>
        <city>Minsk</city>
        <zip>220114</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vitebsk Regional Diagnostic Center</name>
      <address>
        <city>Vitebsk</city>
        <zip>210023</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vitebsk Regional Clinical Hospital</name>
      <address>
        <city>Vitebsk</city>
        <zip>210037</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinicl Center Sarajevo</name>
      <address>
        <city>Sarajevo</city>
        <zip>71000</zip>
        <country>Bosnia and Herzegovina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UMHAT Sveti Georgi</name>
      <address>
        <city>Plovdiv</city>
        <zip>4002</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum</name>
      <address>
        <city>Sofia</city>
        <zip>1113</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Multiprofile Hospital For Active Treatment National Cardiology Hospital, Ead</name>
      <address>
        <city>Sofia</city>
        <zip>1309</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Acibadem City Clinic Tokuda Hospital</name>
      <address>
        <city>Sofia</city>
        <zip>1407</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Ivan Rilski University Multiprofile Hospital For Active Treatment</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Multiprofile Hospital for Active Treatment Alexandrovska EAD</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Military Medical Academy, Multiprofile Hospital for Active Treatment -Sofia</name>
      <address>
        <city>Sofia</city>
        <zip>1606</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Alberta</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Jubilee Hospital</name>
      <address>
        <city>Victoria</city>
        <state>British Columbia</state>
        <zip>V8R 1J8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ottawa Hospital</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Recherche Sepmus Inc.</name>
      <address>
        <city>Greenfield Park</city>
        <state>Quebec</state>
        <zip>J4V 2J2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ch Osijek</name>
      <address>
        <city>Osijek</city>
        <zip>31000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Center Zagreb</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultní nemocnici Brno</name>
      <address>
        <city>Brno</city>
        <zip>65691</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultni nemocnice Hradec Kralove</name>
      <address>
        <city>Hradec Králové</city>
        <zip>500 05</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemocnice Jihlava</name>
      <address>
        <city>Jihlava</city>
        <zip>586 33</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultni nemocnice Ostrava</name>
      <address>
        <city>Ostrava-Poruba</city>
        <zip>708 52</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pardubicka krajska nemocnice a.s.</name>
      <address>
        <city>Pardubice</city>
        <zip>532 03</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vseobecna Fakultní Nemocnice</name>
      <address>
        <city>Praha 2</city>
        <zip>128 08</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>FN Motol</name>
      <address>
        <city>Praha 5</city>
        <zip>150 06</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Krajska zdravotni, a.s. - Nemocnice Teplice, o.z.</name>
      <address>
        <city>Teplice</city>
        <zip>415 29</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Suomen Terveystalo Tampere</name>
      <address>
        <city>Tampere</city>
        <zip>33100</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mehilainen NEO</name>
      <address>
        <city>Turku</city>
        <zip>20520</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Pellegrin CHU Bordeaux</name>
      <address>
        <city>Bordeaux cedex</city>
        <zip>33076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Clermont-Ferrand - Hopital Gabriel Montpied</name>
      <address>
        <city>Clermont Ferrand Cedex 1</city>
        <zip>63003</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Nord Laennec - CHU NANTES</name>
      <address>
        <city>Nantes Cedex 1</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital PASTEUR</name>
      <address>
        <city>Nice</city>
        <zip>6000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nouvel Hôpital Civil</name>
      <address>
        <city>Strasbourg CEDEX</city>
        <zip>67091</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>LTD 'Aversi Clinic'</name>
      <address>
        <city>T'bilisi</city>
        <zip>0160</zip>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>P. Sarajishvili Institute of Neurology</name>
      <address>
        <city>Tbilisi</city>
        <zip>112</zip>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pineo Medical Ecosystem Ltd</name>
      <address>
        <city>Tbilisi</city>
        <zip>114</zip>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>S.Khechinashvili University Hospital</name>
      <address>
        <city>Tbilisi</city>
        <zip>179</zip>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Curatio, Jsc</name>
      <address>
        <city>Tbilisi</city>
        <zip>186</zip>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Carl-Gustav-Carus Dresden</name>
      <address>
        <city>Dresden</city>
        <zip>1307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helios Klinikum Erfurt</name>
      <address>
        <city>Erfurt</city>
        <zip>99089</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Panakeia - Arzneimittelforschung GmbH</name>
      <address>
        <city>Leipzig</city>
        <zip>04275</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin der Johannes Gutenberg-Universität Mainz</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>401 Military Hospital</name>
      <address>
        <city>Athens</city>
        <zip>115 25</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Naval Hospital of Athens</name>
      <address>
        <city>Athens</city>
        <zip>11521</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Center of Athens</name>
      <address>
        <city>Marousi</city>
        <zip>15125</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uzsoki Utcai Korhaz</name>
      <address>
        <city>Budapest</city>
        <zip>1145</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jahn Ferenc Del-pesti Korhaz es Rendelointezet</name>
      <address>
        <city>Budapest</city>
        <zip>1204</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Valeomed EGÉSZSÉGÜGYI KÖZPONT</name>
      <address>
        <city>Esztergom</city>
        <zip>2500</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Petz Aladar Megyei Oktato Korhaz</name>
      <address>
        <city>Győr</city>
        <zip>9023</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pest Megyei Flor Ferenc Korhaz</name>
      <address>
        <city>Kistarcsa</city>
        <zip>2143</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barzilai Medical Center</name>
      <address>
        <city>Ashkelon</city>
        <zip>7830604</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Medical Center</name>
      <address>
        <city>Haifa</city>
        <zip>3109601</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hadassah Medical Center</name>
      <address>
        <city>Jerusalem</city>
        <zip>9112001</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ziv Medical Center</name>
      <address>
        <city>Safed</city>
        <zip>1304300</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale San Salvatore</name>
      <address>
        <city>L' Aquila</city>
        <zip>67100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Sant Andrea</name>
      <address>
        <city>Roma</city>
        <zip>189</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pauls Stradins Clinical University Hospital</name>
      <address>
        <city>Riga</city>
        <zip>1002</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Latvias Juras medicinas centrs Ltd</name>
      <address>
        <city>Riga</city>
        <zip>1015</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rīgas Austrumu klīniskā universitātes slimnīca</name>
      <address>
        <city>Riga</city>
        <zip>LV-1038</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital of Lithuanian University of Health Sciences Kaunas Clinics</name>
      <address>
        <city>Kaunas</city>
        <zip>LT50161</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VsI Respublikine Siauliu ligonine, V.</name>
      <address>
        <city>Šiauliai</city>
        <zip>76231</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Unidad de Investigacion En Salud</name>
      <address>
        <city>Chihuahua</city>
        <zip>31203</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CRI Centro Regiomontano de Investigacion SC</name>
      <address>
        <city>Nuevo Leon</city>
        <zip>64060</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurocentrum Bydgoszcz Sp Z O O</name>
      <address>
        <city>Bydgoszcz</city>
        <zip>85-796</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Copernicus Podmiot Leczniczy Sp. z o.o</name>
      <address>
        <city>Gdansk</city>
        <zip>80-803</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NeuroCentrum. Centrum Terapii SM</name>
      <address>
        <city>Katowice</city>
        <zip>40-571</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NEURO-MEDIC Janusz Zbrojkiewicz Poradnia Wielospecjalistyczna</name>
      <address>
        <city>Katowice</city>
        <zip>40-686</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Kompleksowej Rehabilitacji</name>
      <address>
        <city>Konstancin-Jeziorna</city>
        <zip>05-510</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Opieki Zdrowotnej Orkan-Med</name>
      <address>
        <city>Ksawerow</city>
        <zip>95-054</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indywidualna Praktyka Lekarska Prof. Konrad Rejdak</name>
      <address>
        <city>Lublin</city>
        <zip>20-015</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Szpital Kliniczny im. Heliodora Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Po</name>
      <address>
        <city>Poznan</city>
        <zip>60-355</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research Center sp. z o.o MEDIC-R s.k.</name>
      <address>
        <city>Poznan</city>
        <zip>61-731</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partnerska Lekarzy</name>
      <address>
        <city>Poznan</city>
        <zip>61-853</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>WroMedica I.Bielicka, A.Strzałkowska s.c.</name>
      <address>
        <city>Wrocław</city>
        <zip>51-685</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de Braga</name>
      <address>
        <city>Braga</city>
        <zip>4710-243</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospitais da universidade de Coimbra</name>
      <address>
        <city>Coimbra</city>
        <zip>3000-075</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hosp. Cuf Descobertas</name>
      <address>
        <city>Lisboa</city>
        <zip>1998-018</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Santo António - Centro Hospitalar do Porto</name>
      <address>
        <city>Porto</city>
        <zip>4099-001</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spitalul Universitar de Urgenta Militar Central 'Dr. Carol Davila'</name>
      <address>
        <city>Bucuresti</city>
        <zip>10825</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institutul Clinic Fundeni</name>
      <address>
        <city>Bucuresti</city>
        <zip>22328</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spitalul Universitar de Urgenta Bucuresti</name>
      <address>
        <city>Bucuresti</city>
        <zip>50098</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spitalul Clinic Judetean de Urgenta 'Pius Brinzeu'</name>
      <address>
        <city>Timisoara</city>
        <zip>300723</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barnaul Territorial Clinical Hospital</name>
      <address>
        <city>Barnaul, Altai Krai</city>
        <zip>656024</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph Belgorod Regional Hospital</name>
      <address>
        <city>Belgorod</city>
        <zip>308007</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bryansk Regional Hospital #1</name>
      <address>
        <city>Bryansk</city>
        <zip>241033</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sverdlovsk Region Clinical Hospital #1</name>
      <address>
        <city>Ekaterinburg</city>
        <zip>620102</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Medical Center Your Health</name>
      <address>
        <city>Kazan</city>
        <zip>420097</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Federal State Budgetary Institution</name>
      <address>
        <city>Krasnoyarsk</city>
        <zip>660037</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Budgetary Healthcare Institution Kursk Region Kursk Regional Clinical Hospital</name>
      <address>
        <city>Kursk</city>
        <zip>305007</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical City Hospital #1</name>
      <address>
        <city>Moscow</city>
        <zip>117049</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Health Care Institution Of Moscow</name>
      <address>
        <city>Moscow</city>
        <zip>127015</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Clinical Hospital N.A.Semashko</name>
      <address>
        <city>Moscow</city>
        <zip>129128</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Municipal Clinical Hospital # 3</name>
      <address>
        <city>Nizhniy Novgorod</city>
        <zip>603155</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siberian District Medical Center of Federal Medical-Biological Agency</name>
      <address>
        <city>Novosibirsk</city>
        <zip>630007</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Federal Scientific Clinical Center of Physico-Chemical Medicine</name>
      <address>
        <city>Odintsovo</city>
        <zip>143000</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Perm State Medical Academy n.a. E. A. Vagner</name>
      <address>
        <city>Perm</city>
        <zip>614990</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City Clinical Hospital # 2</name>
      <address>
        <city>Pyatigorsk</city>
        <zip>357538</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pavlov First Saint Petersburg State Medical University</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Healthcare Institution Samara Regional Clinical Hospital named after V.D.Seredavin</name>
      <address>
        <city>Samara</city>
        <zip>443095</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smolensk Regional Clinical Hospital</name>
      <address>
        <city>Smolensk</city>
        <zip>214018</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Municipal Multi-Specialty Hospital # 2</name>
      <address>
        <city>St. Petersburg</city>
        <zip>194354</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City Clinical Hospital #31</name>
      <address>
        <city>St. Petersburg</city>
        <zip>197110</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Human Brain Ras</name>
      <address>
        <city>St. Petersburg</city>
        <zip>197376</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City Hospital# 40</name>
      <address>
        <city>St.Petersburg</city>
        <zip>197706</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siberian State Medical University</name>
      <address>
        <city>Tomsk</city>
        <zip>634050</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tver Regional Clinical Hospital</name>
      <address>
        <city>Tver</city>
        <zip>170036</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GUZ Novgorod Regional Clinical Hospital</name>
      <address>
        <city>Velikiy Novgorod</city>
        <zip>214018</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yaroslavl Clinical Hospital #8</name>
      <address>
        <city>Yaroslavl</city>
        <zip>150003</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Hospital Center Zvezdara</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vojnomedicinska Akademija</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinical Center Kragujevac</name>
      <address>
        <city>Kragujevac</city>
        <zip>34000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinical Center NIS</name>
      <address>
        <city>Nis</city>
        <zip>18000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital del Mar</name>
      <address>
        <city>Barcelona</city>
        <zip>8003</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Vall d'Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>8035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinic I Provincial</name>
      <address>
        <city>Barcelona</city>
        <zip>8036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de La Princesa</name>
      <address>
        <city>Madrid</city>
        <zip>28006</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Regional Universitario de Malaga</name>
      <address>
        <city>Malaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen Macarena</name>
      <address>
        <city>Sevilla</city>
        <zip>41009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Vithas Nisa Sevilla</name>
      <address>
        <city>Sevilla</city>
        <zip>41950</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sahlgrenska Universitetsjukhuset</name>
      <address>
        <city>Göteborg</city>
        <zip>413 45</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum för Neurologi</name>
      <address>
        <city>Stockholm</city>
        <zip>113 65</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karadeniz Teknik University Medical Faculty</name>
      <address>
        <city>Trabzon</city>
        <zip>61080</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Public Non-profit Enterprise: Chernihiv City Hospital #4 under Chernihiv City Council</name>
      <address>
        <city>Chernihiv</city>
        <zip>14001</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Municipal health care institution Chernihiv Regional Hospital</name>
      <address>
        <city>Chernihiv</city>
        <zip>14029</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ivano-Frankivsk Regional Clinical Hospital</name>
      <address>
        <city>Ivano-Frankivsk</city>
        <zip>76018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Limited Liability Company 'Neuro Global'</name>
      <address>
        <city>Ivano-Frankivsk</city>
        <zip>76493</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kharkiv Railway Clinical Hospital N1 Of Brance 'Health Center'</name>
      <address>
        <city>Kharkiv</city>
        <zip>61103</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kharkiv Postgrad Academy, Dept of Neurology #1 At Hosp #7</name>
      <address>
        <city>Kharkiv</city>
        <zip>61176</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Research Center for Radiation Medicine</name>
      <address>
        <city>Kyiv</city>
        <zip>3115</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Public Non-Profit Enterprise: Lviv City Clinical Hospital #5</name>
      <address>
        <city>Lviv</city>
        <zip>79000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lviv Clinical Regional Hospital</name>
      <address>
        <city>Lviv</city>
        <zip>79010</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Odessa National Medical University</name>
      <address>
        <city>Odesa</city>
        <zip>65009</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ME 'Poltava Regional Clinical Hospital n.a. M.V. Sklifosovsky of the Poltava Regional Council'</name>
      <address>
        <city>Poltava</city>
        <zip>36024</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mnce 'Ternopil Regional Clinical Psychoneurology Hospital' of Trb</name>
      <address>
        <city>Ternopil</city>
        <zip>46027</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Center Salutem LLC</name>
      <address>
        <city>Vinnytsia</city>
        <zip>21000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>O.F. Herbachevskyi Regional Clinical Hospital</name>
      <address>
        <city>Zhytomyr</city>
        <zip>10008</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Preston Hospital</name>
      <address>
        <city>Preston</city>
        <zip>PR2 9HT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Salford Royal NHS Foundation Trust</name>
      <address>
        <city>Salford</city>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belarus</country>
    <country>Bosnia and Herzegovina</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>Croatia</country>
    <country>Czechia</country>
    <country>Finland</country>
    <country>France</country>
    <country>Georgia</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Latvia</country>
    <country>Lithuania</country>
    <country>Mexico</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Romania</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Turkey</country>
    <country>Ukraine</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 20, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2017</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ponesimod</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03232073
org study id: AC-058B303
secondary id: 2016-004719-10
nct id: NCT03232073
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The study AC-058B301 (OPTIMUM; NCT02425644) has been designed to investigate the efficacy,
      safety and tolerability of ponesimod in subjects with relapsing multiple sclerosis (RMS). The
      AC-058B303 study is the long-term extension for the core study AC-058B301. The purpose of
      this long term extension of the core study AC-058B301 is to characterize the long-term
      safety, tolerability, and control of disease of ponesimod 20 mg in subjects with RMS.
The AC-058B303 study (extension study) is the long-term extension for the AC-058B301 study
      (core study). The core study has been designed to investigate the efficacy, safety and
      tolerability of ponesimod in subjects with RMS. The subjects are treated with either
      ponesimod or the active comparator, teriflunomide in the core study. The purpose of this long
      term extension of the core study is to characterize the long-term safety and control of
      disease of ponesimod in subjects with RMS. In particular, the study will allow to observe
      potential adverse events which may only occur after long term treatment with ponesimod. The
      study will also investigate the effect of re-initiation of ponesimod after a brief
      interruption in a relatively large population (all subjects treated with ponesimod in the
      core study and eligible for the extension study) on disease activity in terms of relapses and
      MS-related MRI lesions. There is currently limited guidance on when a new MS treatment should
      be started after discontinuation of teriflunomide and the study will contribute with data on
      safety and efficacy of switching from teriflunomide to ponesimod after an interruption as
      mandated by the protocol. The study will also allow confirmation of sustained efficacy of
      ponesimod in terms of relapses, MRI lesions and reduction of disability accumulation during
      long-term treatment. In addition, combined data from the core study together with the results
      of the current extension study will allow comparison of MS activity in subjects who were
      switched from teriflunomide to ponesimod versus those who were treated with ponesimod in both
      studies. A vaccination sub-study will be conducted in a sub-set of up to 50 eligible study
      participants from selected countries who consent to be vaccinated with the Janssen
      coronavirus disease-2019 (COVID-19) vaccine (Ad26.COV2.S) to investigate the immune response
      induced by the Janssen COVID-19 vaccine.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a single-group open-label extension study to investigate long-term safety, tolerability and control of disease of ponesimod 20 mg in subjects with RMS. Statistical analyses will be descriptive and therefore all endpoints are exploratory in nature. All exploratory endpoints are listed under primary outcomes.
primary purpose: Treatment
masking: None (Open Label)
measure: Annualized confirmed relapse rate (ARR)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: defined as the number of confirmed relapses per subject-year
measure: Time from core study randomization to first confirmed relapse
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Time from enrollment in core study to first confirmed relapse
measure: Time to first 12-week confirmed disability accumulation (CDA)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Time from core baseline to first 12-week CDA
measure: Time to first 24-week confirmed disability accumulation (CDA)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Time from core baseline to first 24-week CDA
measure: Patients with absence of relapses
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Number of patients with absence of relapses during study period
measure: Change from baseline in Expanded Disability Status Scale (EDSS)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Change from baseline in EDSS at all assessments
measure: Assessment of no evidence of disease activity (NEDA) status at end-of-study (EOS) according to NEDA 3
time frame: Up to 354 weeks
description: NEDA 3 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA
measure: Assessment of no evidence of disease activity (NEDA) status at EOS according to NEDA 4
time frame: Up to 354 weeks
description: NEDA 4 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA, and annual brain volume change ≥ -0.4% from baseline to all assessments
measure: Percent change from baseline in brain volume (PCBV) measured by magnetic resonance imaging (MRI)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Change from baseline in brain volume at all assessments
measure: Cumulative number of combined unique active lesions (CUAL) measured by MRI
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Cumulative number of combined unique active lesions (CUAL) defined as new Gd+ T1 lesions plus new or enlarging T2 lesions (without double-counting the lesions) at all assessments
measure: Determination of number of Gd+ T1 lesions by MRI
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Number of Gd+ T1 lesions at all assessments
measure: Cumulative number of new or enlarging T2 lesions measured by MRI
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Cumulative number of new or enlarging T2 lesions (relative to baseline) at all assessments
measure: Assessment of volume of brain lesions measured by MRI
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Determination of MRI lesions (T2 lesions, T1 hypointense lesions) at all assessments
measure: Absence of MRI lesions
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) at all assessments
measure: Determination of proportion of Gd+ lesions at baseline evolving to persistent black holes (PBHs)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Proportion of Gd+ lesions at baseline evolving to PBHs at all assessments
measure: Estimation of incidence rates of adverse events (AEs)
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Incidence rates of treatment-emergent AEs, severe AEs, AEs of special interest and AEs leading to premature discontinuation of study treatment
measure: Estimation of incidence rates of treatment-emergent morphological ECG abnormalities
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: ECG abnormalities as defined by the ECG provider
measure: Assessment of cardiac rhythms measured by electrocardiogram (ECG) parameters
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Absolute values by visit for 12-lead ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)
measure: Change from baseline values by visit for cardiac rhythms
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Change from baseline values by visit for ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)
measure: Change in ECG parameters from pre-dose to selected post-dose assessments
time frame: Analysis period: From day 1 in extension study to end-of-treatment (EOT) in extension study, i.e. for up to 240 weeks
description: Change in ECG parameters (HR, PR, QRS, QT, QTcB, QTcF) from pre-dose to selected post-dose assessments (1h, 2h, 3h, 4h) on day 1 of extension study and on day of re-initiation of study treatment
measure: Absolute values and percent change from baseline in forced expiratory volume and forced vital capacity
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Absolute values and percent change from baseline in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at all assessments
measure: Assessment of treatment-emergent decrease from baseline in forced expiratory volume and forced vital capacity
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Determination of treatment-emergent decrease from baseline in FEV1 and FVC (absolute and % of predicted)
measure: Absolute change from baseline to end-of-study (EOS) versus change from baseline to end-of-treatment (EOT) in forced expiratory volume and forced vital capacity
time frame: Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks
description: Absolute change from baseline to end-of-study (EOS) versus change from baseline to end-of-treatment (EOT) in FEV1 and FVC (absolute and % of predicted)
arm group label: Ponesimod
arm group type: Experimental
description: 20 mg administered orally once daily
intervention type: Drug
intervention name: Ponesimod
description: Ponesimod; Film-coated tablet; Oral use. From Day 1 to Day 14, ponesimod is gradually up-titrated until a maintenance dose of 20 mg is reached from Day 15
arm group label: Ponesimod
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Tatiana Sidorenko, MD, PhD
role: Study Director
affiliation: Actelion
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country: Belarus
country: Bosnia and Herzegovina
country: Bulgaria
country: Canada
country: Croatia
country: Czechia
country: Finland
country: France
country: Georgia
country: Germany
country: Greece
country: Hungary
country: Israel
country: Italy
country: Latvia
country: Lithuania
country: Mexico
country: Poland
country: Portugal
country: Romania
country: Russian Federation
country: Serbia
country: Spain
country: Sweden
country: Turkey
country: Ukraine
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Ponesimod