<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/NCT04504825</url>
  </required_header>
  <id_info>
    <org_study_id>CAEL101-301</org_study_id>
    <nct_id>NCT04504825</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis</brief_title>
  <official_title>A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIb AL Amyloidosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Alexion</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Alexion</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>
      AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and&#xD;
      create free light chains that cannot be broken down. These free light chains bind together to&#xD;
      form amyloid fibrils that build up in the extracellular space of organs, affecting the&#xD;
      kidneys, heart, liver, spleen, nervous system and digestive tract.&#xD;
&#xD;
      The primary purpose of this study is to determine whether CAEL-101, a monoclonal antibody&#xD;
      that removes AL amyloid deposits from tissues and organs, improves overall survival and it is&#xD;
      safe and well tolerated in patients with stage IIIb AL amyloidosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a double-blind, randomized, multicenter international Phase 3 study of CAEL-101&#xD;
      combined with standard of care (SoC) plasma cell dyscrasia (PCD) treatment versus placebo&#xD;
      combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis&#xD;
      patients. As this is an event-driven study, the study will enroll until at least 101 deaths&#xD;
      have been observed. Approximately 124 patients will be enrolled using a 2:1 randomization&#xD;
      ratio. Stratification will be based on geographic region across investigator sites. An&#xD;
      interim analysis (IA) may be performed when approximately 75% (76/101) of the expected deaths&#xD;
      has been observed.&#xD;
&#xD;
      Patients in both study intervention groups will be followed from randomization until death&#xD;
      from any cause or until the end of study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 2, 2021</start_date>
  <completion_date type="Anticipated">December 14, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 14, 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>
    <intervention_model_description>This is a double-blind, randomized, multicenter, international Phase 3 study of CAEL-101 combined with SoC PCD treatment versus placebo combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. As this is an event-driven study, the study will enroll until at least 101 deaths have been observed. Approximately 124 patients will be enrolled using a 2:1 randomization ratio and stratification will be based on geographic region across investigator sites. An interim analysis (IA) with stopping rules for early efficacy may be performed when approximately 75% (76/101) of the expected deaths have been observed. Patients in both study intervention groups will be followed from randomization until death from any cause or until the end of study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>This is a double-blind, randomized, multicenter international Phase 3 study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time from the date of randomization to date of death or end of study.</measure>
    <time_frame>50 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0</measure>
    <time_frame>50 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of Life (QOL) by the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS)</measure>
    <time_frame>50 weeks</time_frame>
    <description>A 23-item self-administered questionnaire that quantifies physical function, symptoms, social function, self-efficacy and knowledge and quality of life. It requires an average of 4-6 minutes to complete and uses an ordinal, adjectival (Likert) scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac Improvement by Global Longitudinal Strain (GLS%)</measure>
    <time_frame>50 weeks</time_frame>
    <description>To assess improvement in heart function as measured by percent Global Longitudinal Strain (GLS%). GLS% is a non-invasive imaging technique to assess heart function where a higher/lower percentage is indicative of improvement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in distance walked (in meters) during a six-minute walk test (6MWT)</measure>
    <time_frame>50 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life (QOL) by the Short Form-36 (SF-36) v2 Physical Component Score (PCS)</measure>
    <time_frame>50 weeks</time_frame>
    <description>A self-administered questionnaire containing 36 items that measures health on functional status, well-being and overall evaluation of health in 8 domains. It requires approximately 5 minutes to complete and uses scaled, ordinal responses (e.g., All of the time, Most of the time, A good bit of the time, etc.)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for NT-proBNP, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by an increase or decrease in amyloidosis-related biomarkers: NT-proBNP.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of Cardiac troponin (cTnT) in blood samples</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for cTnT, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: cTnT.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of involved/uninvolved free light chain difference (dFLC)</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for dFLC, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: dFLC</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of C-reactive protein (CRP) in blood samples</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for CRP, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: CRP.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of aspartate aminotransferase (AST)</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of alanine aminotransferase (ALT)</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of alkaline phosphatase (ALP)</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of Kidney Glomerular Filtration Rate</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be tested for creatine level that is used to calculate an estimate of how much blood filters through the kidney. A glomeruli filtration rate above 60 mL/min is considered normal.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of Serum Creatinine</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.</description>
  </other_outcome>
  <other_outcome>
    <measure>24-hour Urine Protein Measure</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, urine samples will be collected over a period of 24 hours to determine how much protein is in your urine. Increasing levels of protein suggest decreasing kidney function.</description>
  </other_outcome>
  <other_outcome>
    <measure>Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores</measure>
    <time_frame>50 weeks</time_frame>
    <description>A self-administered questionnaire containing 36 items that measures health on functional status, well-being and overall evaluation of health in 8 domains. It requires approximately 5 minutes to complete and uses scaled, ordinal responses (e.g., All of the time, Most of the time, A good bit of the time, etc.). Changes in the different domains can help assess the benefit or challenges of the disease and your treatment.</description>
  </other_outcome>
  <other_outcome>
    <measure>EuroQual 5-dimension health survey (EQ-5D-5L™)</measure>
    <time_frame>50 weeks</time_frame>
    <description>The EQ-5D-5L™ is a descriptive system assessing mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Patients are asked to indicate the status of each of the dimensions by selecting one of the three levels (no problems, some problems, and extreme problems). The responses are compiled to create a 5-digit number that describe the patient's health state. The EQ-5D-5L™ includes a visual analogue scale for the patient to rate their health that reflects the patient's judgement of their own health. Changes in the different dimensions can help assess the benefit or challenges of the disease and your treatment.</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure of Plasma Levels of CAEL-101</measure>
    <time_frame>50 weeks</time_frame>
    <description>For each subject, blood sample will be assayed for the plasma levels of CAEL-101 to determine how much is in the blood and how long it stays in the blood.</description>
  </other_outcome>
  <other_outcome>
    <measure>Determination of immunogenicity of CAEL-101</measure>
    <time_frame>50 weeks</time_frame>
    <description>The presence of anti-drug antibodies will be assayed and, if present, further evaluation will confirm positivity for anti-drug antibodies and determine specificity, neutralizing ability, cell-mediated immune response and correlation with clinical responses. These data will help inform the overall treatment assessment.</description>
  </other_outcome>
  <other_outcome>
    <measure>Assessment of limitation during physical activity</measure>
    <time_frame>50 weeks</time_frame>
    <description>Patients will be assessed for the NYHA Functional Classification. The NYHA Functional Classification classifies patients in one of four categories based on their limitations during physical activity; the limitations/symptoms are in regard to normal breathing and varying degrees of shortness of breath and/or angina pain.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">124</enrollment>
  <condition>AL Amyloidosis</condition>
  <arm_group>
    <arm_group_label>CAEL-101 combined with SoC plasma cell dyscrasia</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. The minimum planned treatment time for each patient will be at least 50 weeks or until the patient's death. It is planned that all patients will continue their double-blind treatment until the last patient completes at least 50 weeks of treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo combined with SoC plasma cell dyscrasia</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients randomized to receive placebo will receive 0.9% normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250 cc). The minimum planned treatment time for each patient will be at least 50 weeks or until the patient's death. It is planned that all patients will continue their double-blind treatment until the last patient completes at least 50 weeks of treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CAEL-101</intervention_name>
    <description>The investigational product, CAEL-101, is formulated as a sterile liquid solution of protein plus excipients for dilution in a single-use, stoppered, glass vial. Each 10 mL vial contains 300 mg of CAEL-101 at a concentration of 30 mg/mL. CAEL-101 will be diluted with commercially available 0.9% Normal Saline.</description>
    <arm_group_label>CAEL-101 combined with SoC plasma cell dyscrasia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Commercially available 0.9% Normal Saline will be used as the placebo.</description>
    <arm_group_label>Placebo combined with SoC plasma cell dyscrasia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen</intervention_name>
    <description>According to institutional standard of care.</description>
    <arm_group_label>CAEL-101 combined with SoC plasma cell dyscrasia</arm_group_label>
    <arm_group_label>Placebo combined with SoC plasma cell dyscrasia</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  AL amyloidosis stage IIIb based on the European Modification of the 2004 Standard Mayo&#xD;
             Clinic Staging (NT-proBNP &gt; 8,500 ng/L) at the time of Screening&#xD;
&#xD;
          -  Measurable hematologic disease at Screening as defined by at least one of the&#xD;
             following:&#xD;
&#xD;
               1. Involved/uninvolved free light chain difference (dFLC) &gt; 4 mg/dL or&#xD;
&#xD;
               2. Involved free light chain (iFLC) &gt; 4 mg/dL with abnormal Kappa/Lambda ratio or&#xD;
&#xD;
               3. Serum protein electrophoresis (SPEP) m-spike &gt; 0.5 g/dL&#xD;
&#xD;
          -  Histopathological diagnosis of amyloidosis based on polarizing light microscopy of&#xD;
             green bi-refringent material in Congo red stained tissue specimens AND confirmation of&#xD;
             AL derived amyloid deposits by at least one of the following:&#xD;
&#xD;
               1. Immunohistochemistry/Immunofluorescence&#xD;
&#xD;
               2. Mass spectrometry&#xD;
&#xD;
               3. Characteristic electron microscopy appearance/Immunoelectron microscopy&#xD;
&#xD;
          -  Cardiac involvement as defined by:&#xD;
&#xD;
               1. Documented clinical signs and symptoms supportive of a diagnosis of heart failure&#xD;
                  in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an&#xD;
                  alternative explanation for heart failure AND&#xD;
&#xD;
               2. At least one of the following:&#xD;
&#xD;
             i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or ii. Echocardiogram&#xD;
             demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of&#xD;
             &gt; 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic&#xD;
             stenosis), which would adequately explain the degree of wall thickening or iii.&#xD;
             Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of&#xD;
             cardiac amyloidosis&#xD;
&#xD;
          -  Planned first-line treatment for plasma cell dyscrasia is&#xD;
             cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must have a negative pregnancy test during&#xD;
             Screening and must agree to use highly effective contraception from Screening to at&#xD;
             least 5 months following the last study drug administration or 12 months following the&#xD;
             last dose of her PCD therapy, whichever is longer&#xD;
&#xD;
          -  Men must be surgically sterile or must agree to use highly effective contraception and&#xD;
             refrain from donating sperm from Screening to at least 5 months following the last&#xD;
             study drug administration or 12 months following the last dose of their PCD therapy,&#xD;
             whichever is longer&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  Have any other form of amyloidosis other than AL amyloidosis&#xD;
&#xD;
          -  Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2&#xD;
             weeks of a CyBorD-based PCD treatment after Screening laboratory samples are obtained&#xD;
             and prior to randomization is allowed&#xD;
&#xD;
          -  Has POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy,&#xD;
             monoclonal protein and skin changes) syndrome or multiple myeloma defined as clonal&#xD;
             bone marrow plasma cells &gt; 10% from a bone marrow biopsy (performed ≤ 3 months prior&#xD;
             to signing the ICF) or biopsy-proven (performed ≤ 3 months prior to signing the ICF)&#xD;
             bony or extramedullary plasmacytoma AND one or more of the following CRAB features:&#xD;
&#xD;
             a. Evidence of end organ damage that can be attributed to the underlying plasma cell&#xD;
             proliferative disorder, specifically: i. Hypercalcemia: serum calcium &gt; 0.25 mmol/L (&gt;&#xD;
             1 mg/dL) higher than the ULN or &gt; 2.75 mmol/L (&gt; 11 mg/dL) OR ii. Renal insufficiency:&#xD;
             creatinine clearance &lt; 40 mL per minute or serum creatinine &gt; 177 mol/L (&gt; 2 mg/dL) OR&#xD;
             iii. Anemia: hemoglobin value of &gt; 20 g/L below the lowest limit of normal, or a&#xD;
             hemoglobin value &lt; 100 g/L OR iv. Bone lesions: one or more osteolytic lesion on&#xD;
             imaging tests (performed ≤ 3 months prior to signing the ICF): skeletal radiography,&#xD;
             CT, or PET/CT, or MRI. If bone marrow has &lt; 10% clonal plasma cells, more than one&#xD;
             bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow&#xD;
             involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater&#xD;
             clonal plasma cells on bone marrow examination OR ii. More than one focal lesion on&#xD;
             MRI that is at least 5mm or greater in size&#xD;
&#xD;
          -  Have supine systolic blood pressure &lt; 90 mmHg or symptomatic orthostatic hypotension,&#xD;
             defined as a decrease in systolic blood pressure upon standing of &gt; 30 mmHg despite&#xD;
             medical management (e.g., midodrine, fludrocortisones) in the absence of volume&#xD;
             depletion&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wahid Youssef, MD</last_name>
    <role>Study Director</role>
    <affiliation>Alexion, AstraZeneca Rare Disease</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Alexion Pharmaceuticals, Inc</last_name>
    <phone>1-855-752-2356</phone>
    <email>clinicaltrials@alexion.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Weston</city>
        <state>Florida</state>
        <zip>33331</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>New Orleans</city>
        <state>Louisiana</state>
        <zip>70112</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02111</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02118</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599-7295</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27705</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Adelaide</city>
        <zip>SA 5000</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Brisbane</city>
        <zip>QLD 4102</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Murdoch</city>
        <zip>WA 6150</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Sydney</city>
        <zip>NSW 2145</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Linz</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Linz</city>
        <zip>4020</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Bruxelles</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Bruxelles</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Porto Alegre</city>
        <zip>901110</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Recife</city>
        <zip>50040</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Ribeirao Preto</city>
        <zip>14051</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Santo Amaro</city>
        <zip>50040-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Sao Paulo</city>
        <zip>05652-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>São José do Rio Preto</city>
        <zip>15090</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trail Site</name>
      <address>
        <city>São Paulo</city>
        <zip>41253-190</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T2N 4N2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100191</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangzhou</state>
        <zip>510317</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Hangzhou</city>
        <state>Hangzhou</state>
        <zip>310003</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Beijing</city>
        <zip>100034</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Beijing</city>
        <zip>100730</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Hangzhou</city>
        <zip>310009</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Shanghai</city>
        <zip>200011</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Suzhou</city>
        <zip>215004</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Wenzhou</city>
        <zip>325015</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Wuhan</city>
        <zip>430000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Ostrava</city>
        <country>Czechia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Caen</city>
        <zip>14033</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Créteil</city>
        <zip>94010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Marseille</city>
        <zip>13009</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clincal Trial Site</name>
      <address>
        <city>Pessac</city>
        <zip>33604</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Pierre-Bénite</city>
        <zip>69310</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Poitiers</city>
        <zip>86021</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Tours</city>
        <zip>37000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Berlin</city>
        <zip>12203</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Düsseldorf</city>
        <zip>40225</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Hamburg</city>
        <zip>22767</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Münster</city>
        <zip>48149</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Würzburg</city>
        <zip>97080</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Athens</city>
        <zip>11528</zip>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Patras</city>
        <zip>26504</zip>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Thessaloníki</city>
        <zip>546 36</zip>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Haifa</city>
        <zip>31999</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Jerusalem</city>
        <zip>911200</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Petah Tikva</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Ramat Gan</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Tel Aviv</city>
        <zip>6423906</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Brescia</city>
        <zip>25123</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Naples</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Pavia</city>
        <zip>27100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rome</city>
        <zip>00128</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Kumamoto-shi</city>
        <state>Kumamoto</state>
        <zip>860-8556</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Fukushima</city>
        <zip>960-1295</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Nagoya</city>
        <zip>467-8602</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Tokyo</city>
        <zip>150-8935</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Seoul</city>
        <zip>3080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Seoul</city>
        <zip>3722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Seoul</city>
        <zip>6351</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Seoul</city>
        <zip>6591</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Amsterdam</city>
        <zip>1105</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Groningen</city>
        <zip>9713</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>The Hague</city>
        <zip>2545</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Utrecht</city>
        <zip>3584</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Gdansk</city>
        <zip>80-214</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Poznan</city>
        <zip>60-569</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Warszawa</city>
        <zip>02-097</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Moscow</city>
        <zip>125167</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>197341</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Gijon</city>
        <zip>33203</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Granada</city>
        <zip>18014</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Madrid</city>
        <zip>28003</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Madrid</city>
        <zip>28222</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Pamplona</city>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Salamanca</city>
        <zip>37007</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Valencia</city>
        <zip>46009</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Zurich</city>
        <zip>8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Glasgow</city>
        <zip>CH63 4JY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>London</city>
        <zip>NW1 2PG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Brazil</country>
    <country>Canada</country>
    <country>China</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Korea, Republic of</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>August 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>August 10, 2023</last_update_submitted>
  <last_update_submitted_qc>August 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Plasma Cell Dyscrasia</keyword>
  <keyword>cyclophosphamide, bortezomib and dexamethasone (CyBorD)</keyword>
  <keyword>AL Amyloidosis</keyword>
  <keyword>Amyloid, Light chain Amyloidosis</keyword>
  <keyword>treatment-naïve</keyword>
  <keyword>Mayo Stage IIIb</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulin Light-chain Amyloidosis</mesh_term>
    <mesh_term>Paraproteinemias</mesh_term>
    <mesh_term>Amyloidosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Bortezomib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Each patient will be assigned a unique identifier after signing the Informed Consent Form (ICF). Patient numbers will not be reassigned. Any patient records or datasets transferred to the Sponsor must contain only the unique identifier and must not include patient names or any information which would make the patient identifiable. Patients will be informed that their personal study-related data will be used by the Sponsor in accordance with local data protection laws and that their medical records may be examined by representatives of the Sponsor, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) members and by inspectors from regulatory authorities. Study monitors will inspect all documents and records that are required to be maintained by the Investigator for this study.</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/NCT04504825
org study id: CAEL101-301
nct id: NCT04504825
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and
      create free light chains that cannot be broken down. These free light chains bind together to
      form amyloid fibrils that build up in the extracellular space of organs, affecting the
      kidneys, heart, liver, spleen, nervous system and digestive tract.

      The primary purpose of this study is to determine whether CAEL-101, a monoclonal antibody
      that removes AL amyloid deposits from tissues and organs, improves overall survival and it is
      safe and well tolerated in patients with stage IIIb AL amyloidosis.
This is a double-blind, randomized, multicenter international Phase 3 study of CAEL-101
      combined with standard of care (SoC) plasma cell dyscrasia (PCD) treatment versus placebo
      combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis
      patients. As this is an event-driven study, the study will enroll until at least 101 deaths
      have been observed. Approximately 124 patients will be enrolled using a 2:1 randomization
      ratio. Stratification will be based on geographic region across investigator sites. An
      interim analysis (IA) may be performed when approximately 75% (76/101) of the expected deaths
      has been observed.

      Patients in both study intervention groups will be followed from randomization until death
      from any cause or until the end of study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a double-blind, randomized, multicenter, international Phase 3 study of CAEL-101 combined with SoC PCD treatment versus placebo combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. As this is an event-driven study, the study will enroll until at least 101 deaths have been observed. Approximately 124 patients will be enrolled using a 2:1 randomization ratio and stratification will be based on geographic region across investigator sites. An interim analysis (IA) with stopping rules for early efficacy may be performed when approximately 75% (76/101) of the expected deaths have been observed. Patients in both study intervention groups will be followed from randomization until death from any cause or until the end of study.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: This is a double-blind, randomized, multicenter international Phase 3 study.
measure: Time from the date of randomization to date of death or end of study.
time frame: 50 weeks
measure: Number of patients with treatment emergent adverse events as assessed by CTCAE v5.0
time frame: 50 weeks
measure: Quality of Life (QOL) by the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS)
time frame: 50 weeks
description: A 23-item self-administered questionnaire that quantifies physical function, symptoms, social function, self-efficacy and knowledge and quality of life. It requires an average of 4-6 minutes to complete and uses an ordinal, adjectival (Likert) scale
measure: Cardiac Improvement by Global Longitudinal Strain (GLS%)
time frame: 50 weeks
description: To assess improvement in heart function as measured by percent Global Longitudinal Strain (GLS%). GLS% is a non-invasive imaging technique to assess heart function where a higher/lower percentage is indicative of improvement.
measure: Change in distance walked (in meters) during a six-minute walk test (6MWT)
time frame: 50 weeks
measure: Quality of Life (QOL) by the Short Form-36 (SF-36) v2 Physical Component Score (PCS)
time frame: 50 weeks
description: A self-administered questionnaire containing 36 items that measures health on functional status, well-being and overall evaluation of health in 8 domains. It requires approximately 5 minutes to complete and uses scaled, ordinal responses (e.g., All of the time, Most of the time, A good bit of the time, etc.)
measure: Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood samples
time frame: 50 weeks
description: For each subject, blood sample will be assayed for NT-proBNP, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by an increase or decrease in amyloidosis-related biomarkers: NT-proBNP.
measure: Measure of Cardiac troponin (cTnT) in blood samples
time frame: 50 weeks
description: For each subject, blood sample will be assayed for cTnT, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: cTnT.
measure: Measure of involved/uninvolved free light chain difference (dFLC)
time frame: 50 weeks
description: For each subject, blood sample will be assayed for dFLC, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: dFLC
measure: Measure of C-reactive protein (CRP) in blood samples
time frame: 50 weeks
description: For each subject, blood sample will be assayed for CRP, comparing the subject's baseline value over time to assess improvement in the heart by reduced amyloidosis as measured by changes in amyloidosis-related biomarkers: CRP.
measure: Measure of aspartate aminotransferase (AST)
time frame: 50 weeks
description: For each subject, blood sample will be assayed for AST to determine effects on liver function relative to normal values.
measure: Measure of alanine aminotransferase (ALT)
time frame: 50 weeks
description: For each subject, blood sample will be assayed for ALT to determine effects on liver function relative to normal values.
measure: Measure of alkaline phosphatase (ALP)
time frame: 50 weeks
description: For each subject, blood sample will be assayed for ALP to determine effects on liver function relative to normal values.
measure: Measure of Kidney Glomerular Filtration Rate
time frame: 50 weeks
description: For each subject, blood sample will be tested for creatine level that is used to calculate an estimate of how much blood filters through the kidney. A glomeruli filtration rate above 60 mL/min is considered normal.
measure: Measure of Serum Creatinine
time frame: 50 weeks
description: For each subject, blood sample will be assayed for creatinine to determine changes during treatment that reflect kidney function.
measure: 24-hour Urine Protein Measure
time frame: 50 weeks
description: For each subject, urine samples will be collected over a period of 24 hours to determine how much protein is in your urine. Increasing levels of protein suggest decreasing kidney function.
measure: Quality of Life (QoL) by Short Form-36 (SF-36) v2 scaled domain scores
time frame: 50 weeks
description: A self-administered questionnaire containing 36 items that measures health on functional status, well-being and overall evaluation of health in 8 domains. It requires approximately 5 minutes to complete and uses scaled, ordinal responses (e.g., All of the time, Most of the time, A good bit of the time, etc.). Changes in the different domains can help assess the benefit or challenges of the disease and your treatment.
measure: EuroQual 5-dimension health survey (EQ-5D-5L™)
time frame: 50 weeks
description: The EQ-5D-5L™ is a descriptive system assessing mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Patients are asked to indicate the status of each of the dimensions by selecting one of the three levels (no problems, some problems, and extreme problems). The responses are compiled to create a 5-digit number that describe the patient's health state. The EQ-5D-5L™ includes a visual analogue scale for the patient to rate their health that reflects the patient's judgement of their own health. Changes in the different dimensions can help assess the benefit or challenges of the disease and your treatment.
measure: Measure of Plasma Levels of CAEL-101
time frame: 50 weeks
description: For each subject, blood sample will be assayed for the plasma levels of CAEL-101 to determine how much is in the blood and how long it stays in the blood.
measure: Determination of immunogenicity of CAEL-101
time frame: 50 weeks
description: The presence of anti-drug antibodies will be assayed and, if present, further evaluation will confirm positivity for anti-drug antibodies and determine specificity, neutralizing ability, cell-mediated immune response and correlation with clinical responses. These data will help inform the overall treatment assessment.
measure: Assessment of limitation during physical activity
time frame: 50 weeks
description: Patients will be assessed for the NYHA Functional Classification. The NYHA Functional Classification classifies patients in one of four categories based on their limitations during physical activity; the limitations/symptoms are in regard to normal breathing and varying degrees of shortness of breath and/or angina pain.
arm group label: CAEL-101 combined with SoC plasma cell dyscrasia
arm group type: Experimental
description: CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. The minimum planned treatment time for each patient will be at least 50 weeks or until the patient's death. It is planned that all patients will continue their double-blind treatment until the last patient completes at least 50 weeks of treatment.
arm group label: Placebo combined with SoC plasma cell dyscrasia
arm group type: Placebo Comparator
description: Patients randomized to receive placebo will receive 0.9% normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250 cc). The minimum planned treatment time for each patient will be at least 50 weeks or until the patient's death. It is planned that all patients will continue their double-blind treatment until the last patient completes at least 50 weeks of treatment.
intervention type: Drug
intervention name: CAEL-101
description: The investigational product, CAEL-101, is formulated as a sterile liquid solution of protein plus excipients for dilution in a single-use, stoppered, glass vial. Each 10 mL vial contains 300 mg of CAEL-101 at a concentration of 30 mg/mL. CAEL-101 will be diluted with commercially available 0.9% Normal Saline.
arm group label: CAEL-101 combined with SoC plasma cell dyscrasia
intervention type: Other
intervention name: Placebo
description: Commercially available 0.9% Normal Saline will be used as the placebo.
arm group label: Placebo combined with SoC plasma cell dyscrasia
intervention type: Drug
intervention name: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen
description: According to institutional standard of care.
arm group label: CAEL-101 combined with SoC plasma cell dyscrasia
arm group label: Placebo combined with SoC plasma cell dyscrasia
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wahid Youssef, MD
role: Study Director
affiliation: Alexion, AstraZeneca Rare Disease
last name: Alexion Pharmaceuticals, Inc
phone: 1-855-752-2356
email: clinicaltrials@alexion.com
facility: 
status: Recruiting
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status: Withdrawn
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status: Recruiting
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status: Withdrawn
facility: 
status: Not yet recruiting
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status: Not yet recruiting
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status: Recruiting
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status: Not yet recruiting
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status: Not yet recruiting
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status: Not yet recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Not yet recruiting
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status: Withdrawn
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status: Recruiting
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status: Recruiting
country: Australia
country: Austria
country: Belgium
country: Brazil
country: Canada
country: China
country: Czechia
country: France
country: Germany
country: Greece
country: Israel
country: Italy
country: Japan
country: Korea, Republic of
country: Netherlands
country: Poland
country: Russian Federation
country: Spain
country: Switzerland
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Immunoglobulin Light-chain Amyloidosis
mesh term: Paraproteinemias
mesh term: Amyloidosis
mesh term: Dexamethasone
mesh term: Cyclophosphamide
mesh term: Bortezomib
sharing ipd: Yes
ipd description: Each patient will be assigned a unique identifier after signing the Informed Consent Form (ICF). Patient numbers will not be reassigned. Any patient records or datasets transferred to the Sponsor must contain only the unique identifier and must not include patient names or any information which would make the patient identifiable. Patients will be informed that their personal study-related data will be used by the Sponsor in accordance with local data protection laws and that their medical records may be examined by representatives of the Sponsor, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) members and by inspectors from regulatory authorities. Study monitors will inspect all documents and records that are required to be maintained by the Investigator for this study.