<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/NCT04456673</url>
  </required_header>
  <id_info>
    <org_study_id>EFC15805</org_study_id>
    <secondary_id>2018-001954-91</secondary_id>
    <secondary_id>U1111-1211-8837</secondary_id>
    <nct_id>NCT04456673</nct_id>
  </id_info>
  <brief_title>Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate to Severe COPD With Type 2 Inflammation</brief_title>
  <acronym>NOTUS</acronym>
  <official_title>A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal Study to Assess the Efficacy, Safety, and Tolerability of Dupilumab in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD) With Type 2 Inflammation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Regeneron Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </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 evaluate the efficacy of dupilumab administered every 2 weeks in patients with moderate or&#xD;
      severe Chronic Obstructive Pulmonary Disease (COPD) as measured by&#xD;
&#xD;
        -  Annualized rate of acute moderate or severe COPD exacerbation (AECOPD)&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
      To evaluate the effect of dupilumab administered every 2 weeks on&#xD;
&#xD;
        -  Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared to&#xD;
           placebo&#xD;
&#xD;
        -  Health related quality of life, assessed by the change from baseline to Week 52 in the&#xD;
           St. George's Respiratory Questionnaire (SGRQ)&#xD;
&#xD;
        -  Pre-bronchodilator FEV1 over 52 weeks compared to placebo&#xD;
&#xD;
        -  Lung function assessments&#xD;
&#xD;
        -  Moderate and severe COPD exacerbations&#xD;
&#xD;
        -  To evaluate safety and tolerability&#xD;
&#xD;
        -  To evaluate dupilumab systemic exposure and incidence of antidrug antibodies (ADA)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and&#xD;
      12 weeks of follow-up&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 12, 2020</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">May 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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annual rate of acute COPD exacerbation (AECOPD)</measure>
    <time_frame>Baseline to week 52</time_frame>
    <description>Annualized rate of moderate or severe COPD exacerbations over the 52-week treatment period compared to placebo</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in pre-bronchodilator FEV1</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>Change in pre-bronchodilator FEV1 from baseline to Week 12 compared to placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in SGRQ</measure>
    <time_frame>Baseline to week 52</time_frame>
    <description>Change from baseline to Week 52 in SGRQ total score compared to placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement in SGRQ</measure>
    <time_frame>Baseline to week 52</time_frame>
    <description>Proportion of patients with SGRQ improvement ≥4 points at Week 52</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pre-bronchodilator FEV1 from baseline to Week 52</measure>
    <time_frame>Baseline to week 52</time_frame>
    <description>Change in pre-bronchodilator FEV1 from baseline to Week 52 compared to placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pre-bronchodilator FEV1 from baseline to time points up to Week 44</measure>
    <time_frame>Baseline to weeks 2, 4, 8, 24, 36, 44</time_frame>
    <description>Change in pre-bronchodilator FEV1 from baseline to weeks other than 12 and 52 (i.e. Weeks 2, 4, 8, 24, 36, and 44) compared to placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in post-bronchodilator FEV1 lung function</measure>
    <time_frame>Baseline to weeks 2, 4, 8, 12, 24, 36, 52</time_frame>
    <description>Change in post-bronchodilator FEV1 from baseline at Weeks 2, 4, 8, 12, 24, 36 and 52 compared to placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in forced expiratory flow (FEF) 25-75%</measure>
    <time_frame>Baseline to weeks 2, 4, 8, 12, 24, 36, 44, 52</time_frame>
    <description>Change in FEF 25-75% from baseline to Weeks 2, 4, 8, 12, 24, 36, 44 and 52</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annualized rate of severe AECOPD</measure>
    <time_frame>Baseline through week 52</time_frame>
    <description>Annualized rate of severe COPD exacerbations compared to placebo over the 52-week treatment period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first AECOPD</measure>
    <time_frame>Baseline through week 52</time_frame>
    <description>Time to first moderate or severe COPD exacerbation compared with placebo during the 52-week treatment period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>Baseline through week 64</time_frame>
    <description>Number of adverse events (AEs)/treatment-emergent adverse events (TEAEs)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Potentially clinically significant abnormality (PCSA) in laboratory tests</measure>
    <time_frame>Baseline through week 64</time_frame>
    <description>Percentage of patients with at least one incidence of PCSA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-drug antibodies</measure>
    <time_frame>Baseline through week 64</time_frame>
    <description>Incidence of anti-drug antibodies against dupilumab</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">935</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <arm_group>
    <arm_group_label>Dupilumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dupilumab administered every 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo dose administered every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dupilumab SAR231893</intervention_name>
    <description>Pharmaceutical form: Solution for injection&#xD;
Route of administration: Subcutaneous</description>
    <arm_group_label>Dupilumab</arm_group_label>
    <other_name>Dupixent</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Inhaled Corticosteroid</intervention_name>
    <description>Pharmaceutical form: Inhaled Powder&#xD;
Route of administration: Oral inhalation</description>
    <arm_group_label>Dupilumab</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Inhaled Long-Acting Beta Agonist</intervention_name>
    <description>Pharmaceutical form: Inhaled Powder&#xD;
Route of administration: Oral inhalation</description>
    <arm_group_label>Dupilumab</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Inhaled Long-Acting Muscarinic Antagonist</intervention_name>
    <description>Pharmaceutical form: Inhaled Powder&#xD;
Route of administration: Oral inhalation</description>
    <arm_group_label>Dupilumab</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Pharmaceutical form: Solution for injection&#xD;
Route of administration: Subcutaneous</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  Participants with a physician diagnosis of COPD who meet the following criteria at&#xD;
             screening:&#xD;
&#xD;
               -  Current or former smokers with a smoking history of ≥10 pack-years.&#xD;
&#xD;
               -  Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC]&#xD;
                  ratio &lt;0.70 and post-bronchodilator FEV1 % predicted &gt;30% and ≤70%).&#xD;
&#xD;
               -  Medical Research Council (MRC) Dyspnea Scale grade ≥2.&#xD;
&#xD;
               -  Patient-reported history of signs and symptoms of chronic bronchitis (chronic&#xD;
                  productive cough) for 3 months in the year up to screening in the absence of&#xD;
                  other known causes of chronic cough.&#xD;
&#xD;
               -  Documented history of high exacerbation risk defined as exacerbation history of&#xD;
                  ≥2 moderate or ≥1 severe within the year prior to inclusion. At least one&#xD;
                  exacerbation should have occurred while the patient was taking inhaled&#xD;
                  corticosteroid (ICS)/long acting beta agonist (LABA)/long acting muscarinic&#xD;
                  antagonist (LAMA) (or LABA/LAMA if ICS is contraindicated). Moderate&#xD;
                  exacerbations are recorded by the investigator and defined as AECOPD that require&#xD;
                  either systemic corticosteroids (intramuscular, intravenous, or oral) and/or&#xD;
                  antibiotics. One of the two required moderate exacerbations has to require the&#xD;
                  use of systemic corticosteroids. Severe exacerbations are recorded by the&#xD;
                  investigator and defined as AECOPD requiring hospitalization or observation &gt; 24&#xD;
                  hours in emergency department/urgent care facility.&#xD;
&#xD;
               -  Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization&#xD;
                  with a stable dose of medication for ≥1 month prior to Visit 1; Double therapy&#xD;
                  (LABA + LAMA) allowed if ICS is contraindicated.&#xD;
&#xD;
          -  Evidence of Type 2 inflammation: Patients with blood eosinophils ≥300 cells/microliter&#xD;
             at Visit 1.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  COPD diagnosis for less than 12 months prior to randomization.&#xD;
&#xD;
          -  Participants with current diagnosis of asthma according to the Global Initiative for&#xD;
             Asthma (GINA) guidelines, or documented history of asthma.&#xD;
&#xD;
          -  Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis,&#xD;
             interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss&#xD;
             Syndrome etc) or another diagnosed pulmonary or systemic disease associated with&#xD;
             elevated peripheral eosinophil counts.&#xD;
&#xD;
          -  Cor pulmonale, evidence of right cardiac failure.&#xD;
&#xD;
          -  Long-term treatment with oxygen &gt;4.0 L/min OR if a participant requires more than 2.0&#xD;
             L/min in order to maintain oxygen saturation &gt;88%&#xD;
&#xD;
          -  Hypercapnia requiring Bi-level ventilation.&#xD;
&#xD;
          -  AECOPD as defined in inclusion criteria within 4 weeks prior to screening, or during&#xD;
             the screening period.&#xD;
&#xD;
          -  Respiratory tract infection within 4 weeks prior to screening, or during the screening&#xD;
             period.&#xD;
&#xD;
          -  History of, or planned pneumonectomy or lung volume reduction surgery. Patients who&#xD;
             are participating in the acute phase of a pulmonary rehabilitation program, ie, who&#xD;
             started rehabilitation &lt;4 weeks prior to screening (Note: patients in the maintenance&#xD;
             phase of a rehabilitation program can be included).&#xD;
&#xD;
          -  Diagnosis of α-1 anti-trypsin deficiency.&#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>40 Years</minimum_age>
    <maximum_age>85 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>Cullman Research Center, LLC-Site Number:8400095</name>
      <address>
        <city>Cullman</city>
        <state>Alabama</state>
        <zip>35055</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pulmonary &amp; Sleep Associates of Jasper PC-Site Number:8400090</name>
      <address>
        <city>Jasper</city>
        <state>Alabama</state>
        <zip>35501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Scottsboro Quick Care Clinic-Site Number:8400116</name>
      <address>
        <city>Scottsboro</city>
        <state>Alabama</state>
        <zip>35768</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Phoenix Medical Group-Site Number:8400061</name>
      <address>
        <city>Peoria</city>
        <state>Arizona</state>
        <zip>85381</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Advancement Center of Arizona-Site Number:8400107</name>
      <address>
        <city>Tempe</city>
        <state>Arizona</state>
        <zip>85283</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asthma and Allergy Institute-Site Number:8400022</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kern Research, Inc-Site Number:8400031</name>
      <address>
        <city>Bakersfield</city>
        <state>California</state>
        <zip>93301</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NewportNativeMD, Inc-Site Number:8400032</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Prospective Research Innovations, Inc.-Site Number:8400063</name>
      <address>
        <city>Rancho Cucamonga</city>
        <state>California</state>
        <zip>91730</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ACRC Studies-Site Number:8400094</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92119</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of HealthCare Assessment, Inc.-Site Number:8400015</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allianz Research Institute-Site Number:8400007</name>
      <address>
        <city>Westminster</city>
        <state>California</state>
        <zip>92683</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Innovative Clinical Research-Site Number:8400018</name>
      <address>
        <city>Lafayette</city>
        <state>Colorado</state>
        <zip>80026</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Florida Pulmonary Group, PA-Site Number:8400102</name>
      <address>
        <city>Altamonte Springs</city>
        <state>Florida</state>
        <zip>32701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helix Biomedics, LLC-Site Number:8400035</name>
      <address>
        <city>Boynton Beach</city>
        <state>Florida</state>
        <zip>33435</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pioneer Clinical Research-Site Number:8400043</name>
      <address>
        <city>Boynton Beach</city>
        <state>Florida</state>
        <zip>33437</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Synergy Healthcare-Site Number:8400111</name>
      <address>
        <city>Bradenton</city>
        <state>Florida</state>
        <zip>34208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Renaissance Research and Medical Group, Inc-Site Number:8400092</name>
      <address>
        <city>Cape Coral</city>
        <state>Florida</state>
        <zip>33991</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Francis Sleep, Allergy and Lung Institute-Site Number:8400020</name>
      <address>
        <city>Clearwater</city>
        <state>Florida</state>
        <zip>33765</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beautiful Minds Clinical Research Center-Site Number:8400081</name>
      <address>
        <city>Cutler Bay</city>
        <state>Florida</state>
        <zip>33157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Omega Research Consultants, LLC-Site Number:8400021</name>
      <address>
        <city>DeBary</city>
        <state>Florida</state>
        <zip>32713</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sciences Connections, LLC-Site Number:8400133</name>
      <address>
        <city>Doral</city>
        <state>Florida</state>
        <zip>33178</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>InvesClinic, LLC-Site Number:8400039</name>
      <address>
        <city>Fort Lauderdale</city>
        <state>Florida</state>
        <zip>33308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanguard Clinical Research-Site Number:8400047</name>
      <address>
        <city>Fort Myers</city>
        <state>Florida</state>
        <zip>33907</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Finlay Medical Research-Site Number:8400071</name>
      <address>
        <city>Greenacres City</city>
        <state>Florida</state>
        <zip>33467</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Direct Helpers Medical Center Inc-Site Number:8400079</name>
      <address>
        <city>Hialeah</city>
        <state>Florida</state>
        <zip>33012</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>DL Research Solutions Inc-Site Number:8400089</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33155</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Phoenix Medical Research, LLC-Site Number:8400012</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33165</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbus Clinical Services-Site Number:8400062</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33174</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Reed Medical Research-Site Number:8400123</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33176</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>De La Cruz Research Center, LLC-Site Number:8400075</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33184</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Institute for Clinical Research-Site Number:8400129</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32825-4454</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Florida Pulmonary Group, PA-Site Number:8400101</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32825</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Innovation Medical Research Center-Site Number:8400114</name>
      <address>
        <city>Palmetto Bay</city>
        <state>Florida</state>
        <zip>33157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Family Medical Specialists of Florida, PA-Site Number:8400077</name>
      <address>
        <city>Plant City</city>
        <state>Florida</state>
        <zip>33563</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Coastal Pulmonary And Critical Care-Site Number:8400013</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33704</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Pulmonary Research Center-Site Number:8400001</name>
      <address>
        <city>Winter Park</city>
        <state>Florida</state>
        <zip>32789</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Appalachian Clinical Research-Site Number:8400048</name>
      <address>
        <city>Adairsville</city>
        <state>Georgia</state>
        <zip>30103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northlake Medical Group-Site Number:8400099</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30345</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>River Birch Research, LLC-Site Number:8400045</name>
      <address>
        <city>Blue Ridge</city>
        <state>Georgia</state>
        <zip>30513</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Centre of Conyers-Site Number:8400064</name>
      <address>
        <city>Conyers</city>
        <state>Georgia</state>
        <zip>30094</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>David Kavtaradze MD, Inc.-Site Number:8400135</name>
      <address>
        <city>Cordele</city>
        <state>Georgia</state>
        <zip>31015</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gwinnett Biomedical Research-Site Number:8400052</name>
      <address>
        <city>Lawrenceville</city>
        <state>Georgia</state>
        <zip>30046</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southeast Lung Associates-Site Number:8400003</name>
      <address>
        <city>Rincon</city>
        <state>Georgia</state>
        <zip>31326</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herman Clinical Research LLC-Site Number:8400078</name>
      <address>
        <city>Suwanee</city>
        <state>Georgia</state>
        <zip>30024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Qualmedica Research, LLC-Site Number:8400119</name>
      <address>
        <city>Evansville</city>
        <state>Indiana</state>
        <zip>47715</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Avant Research Associates LLC-Site Number:8400118</name>
      <address>
        <city>Crowley</city>
        <state>Louisiana</state>
        <zip>70526</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Genesis Clinical Research &amp; Consulting-Site Number:8400050</name>
      <address>
        <city>Fall River</city>
        <state>Massachusetts</state>
        <zip>02723</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Infinity Medical Research-Site Number:8400004</name>
      <address>
        <city>South Dartmouth</city>
        <state>Massachusetts</state>
        <zip>02747</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry Ford Health System-Site Number:8400053</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Revive Research Institute-Site Number:8400120</name>
      <address>
        <city>Lathrup Village</city>
        <state>Michigan</state>
        <zip>48076</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Romedica, LLC-Site Number:8400034</name>
      <address>
        <city>Rochester</city>
        <state>Michigan</state>
        <zip>48307</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Covenant Healthcare-Site Number:8400057</name>
      <address>
        <city>Saginaw</city>
        <state>Michigan</state>
        <zip>48638</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Great Lakes Research Institute-Site Number:8400096</name>
      <address>
        <city>Southfield</city>
        <state>Michigan</state>
        <zip>48075</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montana Medical Research-Site Number:8400019</name>
      <address>
        <city>Missoula</city>
        <state>Montana</state>
        <zip>59808</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Somnos Clinical Research-Site Number:8400016</name>
      <address>
        <city>Lincoln</city>
        <state>Nebraska</state>
        <zip>68510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Quality Clinical Research, Inc.-Site Number:8400073</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jersey City Breathing Center-Site Number:8400137</name>
      <address>
        <city>Jersey City</city>
        <state>New Jersey</state>
        <zip>07304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>WellNow Urgent Care-Site Number:8400132</name>
      <address>
        <city>E. Amherst</city>
        <state>New York</state>
        <zip>14051</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwell Health-Site Number:8400054</name>
      <address>
        <city>New Hyde Park</city>
        <state>New York</state>
        <zip>11040</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mid Hudson Medical Research PLLC-Site Number:8400037</name>
      <address>
        <city>New Windsor</city>
        <state>New York</state>
        <zip>12553-7754</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Great Lakes Medical Research-Site Number:8400044</name>
      <address>
        <city>Westfield</city>
        <state>New York</state>
        <zip>14787</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Onsite Clinical Solutions LLC-Site Number:8400042</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28277</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>LLM Research-Site Number:8400125</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>29577</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research of Gastonia-Site Number:8400010</name>
      <address>
        <city>Gastonia</city>
        <state>North Carolina</state>
        <zip>28054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Monroe Biomedical Research-Site Number:8400087</name>
      <address>
        <city>Monroe</city>
        <state>North Carolina</state>
        <zip>28112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lake Norman Pulmonary and Sleep Medicine - Mooresville-Site Number:8400006</name>
      <address>
        <city>Mooresville</city>
        <state>North Carolina</state>
        <zip>28117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lapis Clinical Research At BlueSkies Family Medicine-Site Number:8400117</name>
      <address>
        <city>Mooresville</city>
        <state>North Carolina</state>
        <zip>28117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Coastal Carolina Health Care, P.A.-Site Number:8400025</name>
      <address>
        <city>New Bern</city>
        <state>North Carolina</state>
        <zip>28562</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southeastern Research Center-Site Number:8400068</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Optimed Research, LTD-Site Number:8400082</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43235</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toledo Institute of Clinical Research-Site Number:8400024</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <zip>43617</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allergy, Asthma and Clinical Research Center-Site Number:8400127</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research of Central PA-Site Number:8400009</name>
      <address>
        <city>DuBois</city>
        <state>Pennsylvania</state>
        <zip>15801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Frontier Clinical Research, LLC-Site Number:8400049</name>
      <address>
        <city>Scottdale</city>
        <state>Pennsylvania</state>
        <zip>15683</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carolina Medical Research, LLC-Site Number:8400026</name>
      <address>
        <city>Clinton</city>
        <state>South Carolina</state>
        <zip>29325</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD First Research-Site Number:8400105</name>
      <address>
        <city>Lancaster</city>
        <state>South Carolina</state>
        <zip>29720</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research of Rock Hill-Site Number:8400138</name>
      <address>
        <city>Rock Hill</city>
        <state>South Carolina</state>
        <zip>29732</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Health Concepts-Site Number:8400027</name>
      <address>
        <city>Rapid City</city>
        <state>South Dakota</state>
        <zip>57702</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pulmonary &amp; Sleep Specialists-Site Number:8400136</name>
      <address>
        <city>Dickson</city>
        <state>Tennessee</state>
        <zip>37055</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trials Center of Middle Tennessee-Site Number:8400066</name>
      <address>
        <city>Franklin</city>
        <state>Tennessee</state>
        <zip>37067</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MultiSpecialty Clinical Research-Site Number:8400110</name>
      <address>
        <city>Johnson City</city>
        <state>Tennessee</state>
        <zip>37601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>REX Clinical Trials-Site Number:8400143</name>
      <address>
        <city>Beaumont</city>
        <state>Texas</state>
        <zip>77701-3713</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinrx Research-Site Number:8400059</name>
      <address>
        <city>Carrollton</city>
        <state>Texas</state>
        <zip>75007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Houston Pulmonary and Sleep Associates-Site Number:8400011</name>
      <address>
        <city>Cypress</city>
        <state>Texas</state>
        <zip>77429</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Biopharma Informatic - Cardiff Avenue - PPDS-Site Number:8400055</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77043-2742</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Prolato Clinical Research Center-Site Number:8400128</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pioneer Research Solutions, Inc.-Site Number:8400070</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77099</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vytalus Medical Group-Site Number:8400139</name>
      <address>
        <city>Kingwood</city>
        <state>Texas</state>
        <zip>77339</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>FMC Science, LLC-Site Number:8400029</name>
      <address>
        <city>Lampasas</city>
        <state>Texas</state>
        <zip>76550-1820</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>DCOL Center for Clinical Research-Site Number:8400028</name>
      <address>
        <city>Longview</city>
        <state>Texas</state>
        <zip>75605</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Metroplex Pulmonary and Sleep Center-Site Number:8400131</name>
      <address>
        <city>McKinney</city>
        <state>Texas</state>
        <zip>75069</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinrx Research, LLC-Site Number:8400069</name>
      <address>
        <city>Plano</city>
        <state>Texas</state>
        <zip>75024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Diagnostics Research Group-Site Number:8400038</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pulmonary &amp; Sleep Institute, PA - San Antonio-Site Number:8400080</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78258</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mt. Olympus Medical Research-Site Number:8400115</name>
      <address>
        <city>Sugar Land</city>
        <state>Texas</state>
        <zip>77479</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pulmonary Research of Abingdon, LLC-Site Number:8400030</name>
      <address>
        <city>Abingdon</city>
        <state>Virginia</state>
        <zip>24210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research Partners-Site Number:8400040</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23236</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allergy, Asthma &amp; Sinus Center, S.C.-Site Number:8400088</name>
      <address>
        <city>Greenfield</city>
        <state>Wisconsin</state>
        <zip>53228</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320007</name>
      <address>
        <city>Berazategui</city>
        <state>Buenos Aires</state>
        <zip>CP 1884</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320006</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1122AAK</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320004</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1414AIF</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320001</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1425BEN</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320003</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1425FVH</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320010</name>
      <address>
        <city>La Plata</city>
        <state>Buenos Aires</state>
        <zip>B1900BNN</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320013</name>
      <address>
        <city>Lobos</city>
        <state>Buenos Aires</state>
        <zip>7240</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320005</name>
      <address>
        <city>Quilmes</city>
        <state>Ciudad De Buenos Aires</state>
        <zip>B1878FNR</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320011</name>
      <address>
        <city>Cordoba</city>
        <state>Córdoba</state>
        <zip>X5003DCE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320008</name>
      <address>
        <city>Rosario</city>
        <state>Santa Fe</state>
        <zip>S2000DEJ</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320009</name>
      <address>
        <city>Rosario</city>
        <state>Santa Fe</state>
        <zip>S2002OJP</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320002</name>
      <address>
        <city>Buenos Aires</city>
        <zip>C1121ABE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0320012</name>
      <address>
        <city>Launs Este</city>
        <zip>B1824KAJ</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360003</name>
      <address>
        <city>Westmead</city>
        <state>New South Wales</state>
        <zip>2145</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360008</name>
      <address>
        <city>Kent Town</city>
        <state>South Australia</state>
        <zip>5067</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360006</name>
      <address>
        <city>Box Hill</city>
        <state>Victoria</state>
        <zip>3128</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360005</name>
      <address>
        <city>Clayton</city>
        <state>Victoria</state>
        <zip>3168</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0360001</name>
      <address>
        <city>Murdoch</city>
        <state>Western Australia</state>
        <zip>6150</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560002</name>
      <address>
        <city>Edegem</city>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560001</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560003</name>
      <address>
        <city>Liege</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0560004</name>
      <address>
        <city>Mechelen</city>
        <zip>2800</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760019</name>
      <address>
        <city>Salvador</city>
        <state>Bahia</state>
        <zip>40150-150</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760020</name>
      <address>
        <city>Vitoria</city>
        <state>Espírito Santo</state>
        <zip>29055 450</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760011</name>
      <address>
        <city>Belo Horizonte</city>
        <state>Minas Gerais</state>
        <zip>30150-221</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760008</name>
      <address>
        <city>Passo Fundo</city>
        <state>Rio Grande Do Sul</state>
        <zip>99010-120</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760017</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90020-090</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760001</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90160-090</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760006</name>
      <address>
        <city>Blumenau</city>
        <state>Santa Catarina</state>
        <zip>89030-100</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760018</name>
      <address>
        <city>Florianópolis</city>
        <state>Santa Catarina</state>
        <zip>88040-970</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760015</name>
      <address>
        <city>Campinas</city>
        <state>São Paulo</state>
        <zip>13059900</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760007</name>
      <address>
        <city>Santo Andre</city>
        <state>São Paulo</state>
        <zip>09060-870</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760003</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>01228-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760012</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>01229-010</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760021</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>04014-002</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760002</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>05403-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :0760009</name>
      <address>
        <city>Sorocaba</city>
        <state>São Paulo</state>
        <zip>18040-425</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005025</name>
      <address>
        <city>Burgas</city>
        <zip>8000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005021</name>
      <address>
        <city>Dupnitsa</city>
        <zip>2600</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005012</name>
      <address>
        <city>Haskovo</city>
        <zip>6305</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005011</name>
      <address>
        <city>Montana</city>
        <zip>3400</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005008</name>
      <address>
        <city>Plovdiv</city>
        <zip>4002</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005015</name>
      <address>
        <city>Ruse</city>
        <zip>70000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005013</name>
      <address>
        <city>Ruse</city>
        <zip>7002</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005018</name>
      <address>
        <city>Sofia</city>
        <zip>1000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005003</name>
      <address>
        <city>Sofia</city>
        <zip>1142</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005001</name>
      <address>
        <city>Sofia</city>
        <zip>1233</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005006</name>
      <address>
        <city>Sofia</city>
        <zip>1233</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005002</name>
      <address>
        <city>Sofia</city>
        <zip>1407</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005026</name>
      <address>
        <city>Sofia</city>
        <zip>1618</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005024</name>
      <address>
        <city>Stara Zagora</city>
        <zip>6000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005004</name>
      <address>
        <city>Stara Zagora</city>
        <zip>6001</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005023</name>
      <address>
        <city>Veliko Tyrnovo</city>
        <zip>5000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005027</name>
      <address>
        <city>Veliko Tyrnovo</city>
        <zip>5000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005019</name>
      <address>
        <city>Vidin</city>
        <zip>3700</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1005020</name>
      <address>
        <city>Vratsa</city>
        <zip>3000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240015</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T3L 3E6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240018</name>
      <address>
        <city>Kamloops</city>
        <state>British Columbia</state>
        <zip>V2C 5T1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240017</name>
      <address>
        <city>Kelowna</city>
        <state>British Columbia</state>
        <zip>V1Y 4N7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240014</name>
      <address>
        <city>Moncton</city>
        <state>New Brunswick</state>
        <zip>E1G 5C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240010</name>
      <address>
        <city>Ajax</city>
        <state>Ontario</state>
        <zip>L1S 2J5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240009</name>
      <address>
        <city>Sarnia</city>
        <state>Ontario</state>
        <zip>N7T 4X3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240007</name>
      <address>
        <city>Windsor</city>
        <state>Ontario</state>
        <zip>N8X 1T3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240004</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240012</name>
      <address>
        <city>Québec</city>
        <state>Quebec</state>
        <zip>G1V 4W2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240001</name>
      <address>
        <city>Quebec</city>
        <zip>G1G 3Y8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1240005</name>
      <address>
        <city>Quebec</city>
        <zip>G2J 0C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520009</name>
      <address>
        <city>Valdivia</city>
        <state>Los Ríos</state>
        <zip>5110683</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520006</name>
      <address>
        <city>Curicó</city>
        <state>Maule</state>
        <zip>3341643</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520001</name>
      <address>
        <city>Talca</city>
        <state>Maule</state>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520007</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>7500571</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520003</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>7500692</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520002</name>
      <address>
        <city>Santiago</city>
        <state>Reg Metropolitana De Santiago</state>
        <zip>8910131</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1520004</name>
      <address>
        <city>Quillota</city>
        <state>Valparaíso</state>
        <zip>2260877</zip>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1700002</name>
      <address>
        <city>Bogota</city>
        <zip>11001000</zip>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1700007</name>
      <address>
        <city>Bucaramanga</city>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :1700005</name>
      <address>
        <city>Manizales</city>
        <zip>170004</zip>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030009</name>
      <address>
        <city>Havlickuv Brod</city>
        <zip>580 01</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030004</name>
      <address>
        <city>Jihlava</city>
        <zip>58633</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030001</name>
      <address>
        <city>Jindrichuv Hradec III</city>
        <zip>37701</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030007</name>
      <address>
        <city>Kralupy nad Vltavou</city>
        <zip>278 01</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030003</name>
      <address>
        <city>Miroslav</city>
        <zip>67172</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030010</name>
      <address>
        <city>Nymburk</city>
        <zip>288 01</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030002</name>
      <address>
        <city>Strakonice</city>
        <zip>38601</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2030008</name>
      <address>
        <city>Trutnov</city>
        <zip>541 01</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500009</name>
      <address>
        <city>Bayonne</city>
        <zip>64100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500010</name>
      <address>
        <city>Besancon</city>
        <zip>25030</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500002</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500005</name>
      <address>
        <city>Lyon</city>
        <zip>69004</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500013</name>
      <address>
        <city>Marseille</city>
        <zip>13003</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500004</name>
      <address>
        <city>Marseille</city>
        <zip>13015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500003</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500001</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500007</name>
      <address>
        <city>Paris</city>
        <zip>75014</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500008</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2500006</name>
      <address>
        <city>Pessac</city>
        <zip>33600</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760024</name>
      <address>
        <city>Berlin</city>
        <zip>10969</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760025</name>
      <address>
        <city>Berlin</city>
        <zip>12159</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760017</name>
      <address>
        <city>Darmstadt</city>
        <zip>64283</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760009</name>
      <address>
        <city>Frankfurt am Main</city>
        <zip>60596</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760002</name>
      <address>
        <city>Hamburg</city>
        <zip>20354</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760003</name>
      <address>
        <city>Hannover</city>
        <zip>30173</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760007</name>
      <address>
        <city>Koblenz</city>
        <zip>56068</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760023</name>
      <address>
        <city>Leipzig</city>
        <zip>04299</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760011</name>
      <address>
        <city>Leipzig</city>
        <zip>04347</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760010</name>
      <address>
        <city>Lübeck</city>
        <zip>23552</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760012</name>
      <address>
        <city>Mainz</city>
        <zip>55128</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760008</name>
      <address>
        <city>Marburg</city>
        <zip>35043</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760020</name>
      <address>
        <city>Peine</city>
        <zip>31224</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760016</name>
      <address>
        <city>Rosenheim</city>
        <zip>83022</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :2760018</name>
      <address>
        <city>Wiesbaden</city>
        <zip>65183</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000001</name>
      <address>
        <city>Athens</city>
        <zip>11527</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000005</name>
      <address>
        <city>Athens</city>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000006</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000003</name>
      <address>
        <city>Heraklion</city>
        <zip>71110</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000002</name>
      <address>
        <city>Ioannina</city>
        <zip>455 00</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000007</name>
      <address>
        <city>Palaio Faliro, Athens</city>
        <zip>17562</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3000004</name>
      <address>
        <city>Thessaloniki</city>
        <zip>57010</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480003</name>
      <address>
        <city>Edelény</city>
        <zip>3780</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480004</name>
      <address>
        <city>Gödöllö</city>
        <zip>2100</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480002</name>
      <address>
        <city>Hajdunánás</city>
        <zip>4080</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480006</name>
      <address>
        <city>Mosonmagyaróvár</city>
        <zip>9200</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480005</name>
      <address>
        <city>Szombathely</city>
        <zip>9700</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :3480001</name>
      <address>
        <city>Százhalombatta</city>
        <zip>2440</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280008</name>
      <address>
        <city>Balvi</city>
        <zip>LV-4501</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280007</name>
      <address>
        <city>Rezekne</city>
        <zip>LV - 4601</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280001</name>
      <address>
        <city>Riga</city>
        <zip>LV -1010</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280005</name>
      <address>
        <city>Riga</city>
        <zip>LV -1010</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280006</name>
      <address>
        <city>Riga</city>
        <zip>LV -1021</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280002</name>
      <address>
        <city>Riga</city>
        <zip>LV-1002</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4280003</name>
      <address>
        <city>Riga</city>
        <zip>LV-1038</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400001</name>
      <address>
        <city>Kaunas</city>
        <zip>44320</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400003</name>
      <address>
        <city>Kaunas</city>
        <zip>49449</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400008</name>
      <address>
        <city>Kaunas</city>
        <zip>50161</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400007</name>
      <address>
        <city>Klaipeda</city>
        <zip>92231</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4400005</name>
      <address>
        <city>Vilnius</city>
        <zip>04130</zip>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840008</name>
      <address>
        <city>Benito Juarez</city>
        <state>Ciudad De Mexico</state>
        <zip>03100</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840002</name>
      <address>
        <city>Guadalajara</city>
        <state>Jalisco</state>
        <zip>44100</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840013</name>
      <address>
        <city>Guadalajara</city>
        <state>Jalisco</state>
        <zip>44670</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840011</name>
      <address>
        <city>Zapopan</city>
        <state>Jalisco</state>
        <zip>45070</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840004</name>
      <address>
        <city>Monterrey</city>
        <state>Nuevo León</state>
        <zip>64710</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840003</name>
      <address>
        <city>Monterrey</city>
        <state>Nuevo León</state>
        <zip>66465</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840010</name>
      <address>
        <city>Chihuahua</city>
        <zip>31000</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840006</name>
      <address>
        <city>Durango</city>
        <zip>34000</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840007</name>
      <address>
        <city>Mexico City</city>
        <zip>14050</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840009</name>
      <address>
        <city>Mexico</city>
        <zip>67000</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :4840005</name>
      <address>
        <city>Veracruz</city>
        <zip>91910</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280005</name>
      <address>
        <city>Arnhem</city>
        <zip>6815 AD</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280001</name>
      <address>
        <city>Breda</city>
        <zip>4818 CK</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280010</name>
      <address>
        <city>Dordrecht</city>
        <zip>3318 AT</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280009</name>
      <address>
        <city>Harderwijk</city>
        <zip>3844 DG</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280007</name>
      <address>
        <city>Heerlen</city>
        <zip>6419 PC</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280002</name>
      <address>
        <city>Leeuwarden</city>
        <zip>8934 AD</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280006</name>
      <address>
        <city>Nijmegen</city>
        <zip>6532 SZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280011</name>
      <address>
        <city>Roermond</city>
        <zip>6043 CV</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280008</name>
      <address>
        <city>Zutphen</city>
        <zip>7207 AE</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :5280004</name>
      <address>
        <city>Zwolle</city>
        <zip>8025 AB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6040003</name>
      <address>
        <city>Chancay</city>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6040002</name>
      <address>
        <city>Lima Lima</city>
        <zip>Lima 01</zip>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6040006</name>
      <address>
        <city>Lima</city>
        <zip>021</zip>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6040004</name>
      <address>
        <city>Lima</city>
        <zip>15004</zip>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6040001</name>
      <address>
        <city>Lima</city>
        <zip>LIMA 31</zip>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6040005</name>
      <address>
        <city>Piura</city>
        <zip>20000</zip>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160009</name>
      <address>
        <city>Grudziadz</city>
        <state>Kujawsko-pomorskie</state>
        <zip>86-300</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160007</name>
      <address>
        <city>Krakow</city>
        <state>Malopolskie</state>
        <zip>31-559</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160015</name>
      <address>
        <city>Grodzisk Mazowiecki</city>
        <state>Mazowieckie</state>
        <zip>05-825</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160010</name>
      <address>
        <city>Rzeszow</city>
        <state>Podkarpackie</state>
        <zip>35-205</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160008</name>
      <address>
        <city>Bialystok</city>
        <state>Podlaskie</state>
        <zip>15-044</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160018</name>
      <address>
        <city>Katowice</city>
        <state>Slaskie</state>
        <zip>40-611</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160011</name>
      <address>
        <city>Katowice</city>
        <state>Slaskie</state>
        <zip>40-648</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160022</name>
      <address>
        <city>Ostrowiec Swietokrzyski</city>
        <state>Swietokrzyskie</state>
        <zip>27-400</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160014</name>
      <address>
        <city>Elblag</city>
        <state>Warminsko-mazurskie</state>
        <zip>82-300</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160019</name>
      <address>
        <city>Krakow</city>
        <zip>30-033</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6160020</name>
      <address>
        <city>Nowa Sol</city>
        <zip>67-100</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200007</name>
      <address>
        <city>Almada</city>
        <zip>2801-951</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200006</name>
      <address>
        <city>Aveiro</city>
        <zip>3810-501</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200008</name>
      <address>
        <city>Coimbra</city>
        <zip>3000-075</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200011</name>
      <address>
        <city>Covilhã</city>
        <zip>6200-251</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200002</name>
      <address>
        <city>Guimarães</city>
        <zip>4810-061</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200005</name>
      <address>
        <city>Leiria</city>
        <zip>2410-197</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200009</name>
      <address>
        <city>Lisboa</city>
        <zip>1769</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200012</name>
      <address>
        <city>Matosinhos</city>
        <zip>4464-513</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200003</name>
      <address>
        <city>Porto</city>
        <zip>4099-001</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6200004</name>
      <address>
        <city>Porto</city>
        <zip>4200-319</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6425004</name>
      <address>
        <city>Bacau</city>
        <zip>600252</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6425003</name>
      <address>
        <city>Cluj-Napoca</city>
        <zip>400275</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6425005</name>
      <address>
        <city>Constanta</city>
        <zip>900002</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6425002</name>
      <address>
        <city>Iasi</city>
        <zip>700732</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6425006</name>
      <address>
        <city>Pitesti</city>
        <zip>110117</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6425001</name>
      <address>
        <city>Timisoara</city>
        <zip>300134</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430011</name>
      <address>
        <city>Chelyabinsk</city>
        <zip>454091</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430001</name>
      <address>
        <city>Moscow</city>
        <zip>115093</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430003</name>
      <address>
        <city>Moscow</city>
        <zip>115280</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430002</name>
      <address>
        <city>Moscow</city>
        <zip>125284</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430009</name>
      <address>
        <city>Nizhny Novgorod</city>
        <zip>603126</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430010</name>
      <address>
        <city>Ryazan</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430013</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>198328</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430014</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>928260</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430004</name>
      <address>
        <city>St-Petersburg</city>
        <zip>194354</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430012</name>
      <address>
        <city>Stavropol</city>
        <zip>355020</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430006</name>
      <address>
        <city>Tomsk</city>
        <zip>634034</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430008</name>
      <address>
        <city>Ulyanovsk</city>
        <zip>432017</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6430005</name>
      <address>
        <city>Voronezh</city>
        <zip>394066</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880005</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880006</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880007</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880003</name>
      <address>
        <city>Kragujevac</city>
        <zip>34000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880001</name>
      <address>
        <city>Sremska Kamenica</city>
        <zip>21204</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :6880002</name>
      <address>
        <city>Valjevo</city>
        <zip>14000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030007</name>
      <address>
        <city>Banska Bystrica</city>
        <zip>97517</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030006</name>
      <address>
        <city>Humenne</city>
        <zip>066 01</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030005</name>
      <address>
        <city>Kosice</city>
        <zip>040 01</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030003</name>
      <address>
        <city>Levice</city>
        <zip>93401</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030001</name>
      <address>
        <city>Poprad</city>
        <zip>058 01</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7030002</name>
      <address>
        <city>Spisska Nova Ves</city>
        <zip>05201</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100015</name>
      <address>
        <city>Benoni</city>
        <zip>1500</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100004</name>
      <address>
        <city>Cape Town</city>
        <zip>7500</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100014</name>
      <address>
        <city>Chatsworth</city>
        <zip>4091</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100001</name>
      <address>
        <city>Durban</city>
        <zip>4001</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100013</name>
      <address>
        <city>Durban</city>
        <zip>4001</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100003</name>
      <address>
        <city>Durban</city>
        <zip>4071</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100010</name>
      <address>
        <city>Durban</city>
        <zip>4302</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100002</name>
      <address>
        <city>Gatesville</city>
        <zip>7764</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100009</name>
      <address>
        <city>Johannesburg</city>
        <zip>0157</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100012</name>
      <address>
        <city>Middelburg</city>
        <zip>1050</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100006</name>
      <address>
        <city>Parow</city>
        <zip>7500</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100005</name>
      <address>
        <city>Pretoria</city>
        <zip>0157</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100008</name>
      <address>
        <city>Somerset West</city>
        <zip>7130</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7100011</name>
      <address>
        <city>Vereeniging</city>
        <zip>1935</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240007</name>
      <address>
        <city>Oviedo</city>
        <state>Asturias</state>
        <zip>33011</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240001</name>
      <address>
        <city>Barcelona</city>
        <state>Barcelona [Barcelona]</state>
        <zip>08003</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240002</name>
      <address>
        <city>Barcelona</city>
        <state>Barcelona [Barcelona]</state>
        <zip>08023</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240009</name>
      <address>
        <city>Badalona</city>
        <state>Catalunya [Cataluña]</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240012</name>
      <address>
        <city>Caceres</city>
        <state>Cáceres</state>
        <zip>10002</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240003</name>
      <address>
        <city>Madrid</city>
        <state>Madrid, Comunidad De</state>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240008</name>
      <address>
        <city>Valencia</city>
        <state>Valenciana, Comunidad</state>
        <zip>46017</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240010</name>
      <address>
        <city>Málaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :7240011</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040011</name>
      <address>
        <city>Chernivtsi</city>
        <zip>58001</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040002</name>
      <address>
        <city>Ivano-Frankivsk</city>
        <zip>76018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040003</name>
      <address>
        <city>Ivano-Frankivsk</city>
        <zip>76018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040001</name>
      <address>
        <city>Kharkiv</city>
        <zip>61124</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040007</name>
      <address>
        <city>Kyiv</city>
        <zip>01033</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040004</name>
      <address>
        <city>Kyiv</city>
        <zip>03049</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040006</name>
      <address>
        <city>Lviv</city>
        <zip>79011</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040010</name>
      <address>
        <city>Ternopil</city>
        <zip>46000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040008</name>
      <address>
        <city>Zaporizhzhia</city>
        <zip>69076</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8040009</name>
      <address>
        <city>Zaporizhzhya</city>
        <zip>69600</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260003</name>
      <address>
        <city>Cambridge</city>
        <state>Cambridgeshire</state>
        <zip>CB2 2QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260002</name>
      <address>
        <city>Blackpool</city>
        <state>Lancashire</state>
        <zip>FY3 7DQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260006</name>
      <address>
        <city>Swansea</city>
        <state>Neath Port Talbot</state>
        <zip>SA2 8QA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260007</name>
      <address>
        <city>North Shields</city>
        <state>Newcastle Upon Tyne</state>
        <zip>NE29 8NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260004</name>
      <address>
        <city>South Shields</city>
        <state>Newcastle Upon Tyne</state>
        <zip>NE34 0PL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260013</name>
      <address>
        <city>Nottingham</city>
        <state>Nottinghamshire</state>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260012</name>
      <address>
        <city>Aylesbury</city>
        <zip>HP218AL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260001</name>
      <address>
        <city>Bradford</city>
        <zip>BD9 6RJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260005</name>
      <address>
        <city>Bristol</city>
        <zip>BS10 5NB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260011</name>
      <address>
        <city>Chippenham</city>
        <zip>SN15 2SB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number :8260015</name>
      <address>
        <city>Derby</city>
        <zip>DE223NE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Australia</country>
    <country>Belgium</country>
    <country>Brazil</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>Chile</country>
    <country>Colombia</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>Latvia</country>
    <country>Lithuania</country>
    <country>Mexico</country>
    <country>Netherlands</country>
    <country>Peru</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Romania</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>Slovakia</country>
    <country>South Africa</country>
    <country>Spain</country>
    <country>Ukraine</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.copdclinicalstudies.com/?utm_source=ctgov</url>
    <description>COPD Clinical Studies</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 30, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 2, 2020</study_first_posted>
  <last_update_submitted>June 2, 2023</last_update_submitted>
  <last_update_submitted_qc>June 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 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>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cholinergic Agents</mesh_term>
    <mesh_term>Muscarinic Antagonists</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04456673
org study id: EFC15805
secondary id: 2018-001954-91
secondary id: U1111-1211-8837
nct id: NCT04456673
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Primary Objective:

      To evaluate the efficacy of dupilumab administered every 2 weeks in patients with moderate or
      severe Chronic Obstructive Pulmonary Disease (COPD) as measured by

        -  Annualized rate of acute moderate or severe COPD exacerbation (AECOPD)

      Secondary Objectives:

      To evaluate the effect of dupilumab administered every 2 weeks on

        -  Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared to
           placebo

        -  Health related quality of life, assessed by the change from baseline to Week 52 in the
           St. George's Respiratory Questionnaire (SGRQ)

        -  Pre-bronchodilator FEV1 over 52 weeks compared to placebo

        -  Lung function assessments

        -  Moderate and severe COPD exacerbations

        -  To evaluate safety and tolerability

        -  To evaluate dupilumab systemic exposure and incidence of antidrug antibodies (ADA)
Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and
      12 weeks of follow-up
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Annual rate of acute COPD exacerbation (AECOPD)
time frame: Baseline to week 52
description: Annualized rate of moderate or severe COPD exacerbations over the 52-week treatment period compared to placebo
measure: Change in pre-bronchodilator FEV1
time frame: Baseline to week 12
description: Change in pre-bronchodilator FEV1 from baseline to Week 12 compared to placebo
measure: Change in SGRQ
time frame: Baseline to week 52
description: Change from baseline to Week 52 in SGRQ total score compared to placebo
measure: Improvement in SGRQ
time frame: Baseline to week 52
description: Proportion of patients with SGRQ improvement ≥4 points at Week 52
measure: Change in pre-bronchodilator FEV1 from baseline to Week 52
time frame: Baseline to week 52
description: Change in pre-bronchodilator FEV1 from baseline to Week 52 compared to placebo
measure: Change in pre-bronchodilator FEV1 from baseline to time points up to Week 44
time frame: Baseline to weeks 2, 4, 8, 24, 36, 44
description: Change in pre-bronchodilator FEV1 from baseline to weeks other than 12 and 52 (i.e. Weeks 2, 4, 8, 24, 36, and 44) compared to placebo
measure: Change in post-bronchodilator FEV1 lung function
time frame: Baseline to weeks 2, 4, 8, 12, 24, 36, 52
description: Change in post-bronchodilator FEV1 from baseline at Weeks 2, 4, 8, 12, 24, 36 and 52 compared to placebo
measure: Change in forced expiratory flow (FEF) 25-75%
time frame: Baseline to weeks 2, 4, 8, 12, 24, 36, 44, 52
description: Change in FEF 25-75% from baseline to Weeks 2, 4, 8, 12, 24, 36, 44 and 52
measure: Annualized rate of severe AECOPD
time frame: Baseline through week 52
description: Annualized rate of severe COPD exacerbations compared to placebo over the 52-week treatment period
measure: Time to first AECOPD
time frame: Baseline through week 52
description: Time to first moderate or severe COPD exacerbation compared with placebo during the 52-week treatment period
measure: Adverse events
time frame: Baseline through week 64
description: Number of adverse events (AEs)/treatment-emergent adverse events (TEAEs)
measure: Potentially clinically significant abnormality (PCSA) in laboratory tests
time frame: Baseline through week 64
description: Percentage of patients with at least one incidence of PCSA
measure: Anti-drug antibodies
time frame: Baseline through week 64
description: Incidence of anti-drug antibodies against dupilumab
arm group label: Dupilumab
arm group type: Experimental
description: Dupilumab administered every 2 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo dose administered every 2 weeks
intervention type: Drug
intervention name: Dupilumab SAR231893
description: Pharmaceutical form: Solution for injection
Route of administration: Subcutaneous
arm group label: Dupilumab
other name: Dupixent
intervention type: Drug
intervention name: Inhaled Corticosteroid
description: Pharmaceutical form: Inhaled Powder
Route of administration: Oral inhalation
arm group label: Dupilumab
arm group label: Placebo
intervention type: Drug
intervention name: Inhaled Long-Acting Beta Agonist
description: Pharmaceutical form: Inhaled Powder
Route of administration: Oral inhalation
arm group label: Dupilumab
arm group label: Placebo
intervention type: Drug
intervention name: Inhaled Long-Acting Muscarinic Antagonist
description: Pharmaceutical form: Inhaled Powder
Route of administration: Oral inhalation
arm group label: Dupilumab
arm group label: Placebo
intervention type: Drug
intervention name: Placebo
description: Pharmaceutical form: Solution for injection
Route of administration: Subcutaneous
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 85 Years
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
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country: Argentina
country: Australia
country: Belgium
country: Brazil
country: Bulgaria
country: Canada
country: Chile
country: Colombia
country: Czechia
country: France
country: Germany
country: Greece
country: Hungary
country: Latvia
country: Lithuania
country: Mexico
country: Netherlands
country: Peru
country: Poland
country: Portugal
country: Romania
country: Russian Federation
country: Serbia
country: Slovakia
country: South Africa
country: Spain
country: Ukraine
country: United Kingdom
country: United States
url: http://www.copdclinicalstudies.com/?utm_source=ctgov
description: COPD Clinical Studies
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Inflammation
mesh term: Cholinergic Agents
mesh term: Muscarinic Antagonists
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