<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/NCT02258451</url>
  </required_header>
  <id_info>
    <org_study_id>17096</org_study_id>
    <secondary_id>2014-002114-23</secondary_id>
    <nct_id>NCT02258451</nct_id>
  </id_info>
  <brief_title>Study of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus in Subjects With Bone Predominant HER2 Negative Hormone Receptor Positive Metastatic Breast Cancer</brief_title>
  <official_title>A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bayer</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>
      The objective of this study is to assess efficacy and safety of radium 223 dichloride in&#xD;
      subjects with human epidermal growth factor receptor 2 (HER2) negative hormone receptor&#xD;
      positive breast cancer with bone metastases treated with exemestane and everolimus&#xD;
&#xD;
      After implementation of CSP Amendment 10, only a limited number of subjects will remain in&#xD;
      this study, in order to reduce the burden to study subjects, collection of data will be&#xD;
      reduced and will focus mainly on acute safety, SSE, and OS. Once subjects are rolled over,&#xD;
      the long-term safety will be collected and assessed entirely in the separate extended safety&#xD;
      follow-up study.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 4, 2015</start_date>
  <completion_date type="Actual">October 28, 2022</completion_date>
  <primary_completion_date type="Actual">January 22, 2020</primary_completion_date>
  <phase>Phase 2</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>Symptomatic Skeletal Event-free Survival (SSE-FS)</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>The time from the date of randomization to the date of death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Opiate Use for Cancer Pain</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>Interval from the date of randomization to the date of opiate use</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Pain Progression</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF &quot;Worst pain in 24 hours&quot; score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Cytotoxic Chemotherapy</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>Time from the date of randomization to the date of the first cytotoxic chemotherapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiological Progression-free Survival (rPFS)</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression).&#xD;
Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Pain Improvement</measure>
    <time_frame>Up to 55 months</time_frame>
    <description>In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)</measure>
    <time_frame>From first dosing up to 30 days after the last administration of study treatments, up to 93 months</time_frame>
    <description>An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Post-treatment Chemotherapy Related Adverse Events</measure>
    <time_frame>From post-treatment till end of study, up to 93 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Hematological Oxicities: Worst Grade Under Treatment</measure>
    <time_frame>From first dosing up to 30 days after the last administration of study treatments, up to 93 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With New Primary Malignancies</measure>
    <time_frame>From first dosing till end of study, up to 93 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)</measure>
    <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
    <description>An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Participants With Post-treatment Chemotherapy Related Adverse Events</measure>
    <time_frame>From post-treatment till primary analysis cutoff date, up to 55 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Number of Participants With Hematological Toxicities: Worst Grade Under Treatment</measure>
    <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period</measure>
    <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">283</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Radium-223 dichloride + exemestane/everolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Up to 6 cycles of radium-223 dichloride 50kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + exemestane/everolimus</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Up to 6 cycles of saline injection (placebo) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Radium-223 dichloride (Xofigo, BAY88-8223)</intervention_name>
    <description>Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update)</description>
    <arm_group_label>Radium-223 dichloride + exemestane/everolimus</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo (saline)</intervention_name>
    <description>Up to 6 cycles of saline injection</description>
    <arm_group_label>Placebo + exemestane/everolimus</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Exemestane</intervention_name>
    <description>One 25 mg tablet once daily after a meal.</description>
    <arm_group_label>Placebo + exemestane/everolimus</arm_group_label>
    <arm_group_label>Radium-223 dichloride + exemestane/everolimus</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>The recommended dose of everolimus administered in the study is 10 mg once daily with or without food.&#xD;
Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.</description>
    <arm_group_label>Placebo + exemestane/everolimus</arm_group_label>
    <arm_group_label>Radium-223 dichloride + exemestane/everolimus</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women (≥18 years of age) with metastatic breast cancer not amenable to curative&#xD;
             treatment by surgery or radiotherapy.&#xD;
&#xD;
          -  Documentation of histological or cytological confirmation of estrogen receptor&#xD;
             positive (ER+) and HER2 negative adenocarcinoma of the breast must be available.&#xD;
&#xD;
          -  Documentation of menopausal status: postmenopausal subjects or pre-menopausal subjects&#xD;
             with ovarian radiation or concomitant therapy with a luteinizing hormone-releasing&#xD;
             hormone (LH-RH) agonist/antagonist are eligible.&#xD;
&#xD;
          -  Subjects with bone dominant disease with at least 2 skeletal metastases identified at&#xD;
             baseline by bone scintigraphy and confirmed by computed tomography (CT)/magnetic&#xD;
             resonance imaging (MRI).&#xD;
&#xD;
          -  Subjects must have received at least one line of hormonal therapy in the metastatic&#xD;
             setting.&#xD;
&#xD;
          -  Subjects who are eligible as per the Investigator's assessment and according to the&#xD;
             local label for treatment with exemestane and everolimus as a second line or greater&#xD;
             of hormone therapy in a metastatic setting.&#xD;
&#xD;
          -  Subjects must have experienced recurrent/progressive disease following treatment with&#xD;
             a non-steroidal aromatase inhibitor (letrozole or anastrozole) in an adjuvant or&#xD;
             metastatic setting&#xD;
&#xD;
          -  Subjects must have experienced no more than two skeletal-related events (SREs) prior&#xD;
             to study entry defined as: need for external beam radiotherapy (EBRT) to bone pain,&#xD;
             pathological bone fracture (excluding major trauma), spinal cord compression and/or&#xD;
             orthopedic surgical procedure. Subjects with no prior SREs are not permitted.&#xD;
&#xD;
          -  Subjects must be on therapy with bisphosphonates or denosumab for at least 1 month&#xD;
             before start of study treatment.&#xD;
&#xD;
          -  Adequate hematological, liver and kidney function.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with Inflammatory breast cancer.&#xD;
&#xD;
          -  Patients with immediately life-threatening visceral disease for whom chemotherapy is&#xD;
             preferred treatment option.&#xD;
&#xD;
          -  Subjects who have either received chemotherapy for metastatic disease or are&#xD;
             considered by the treating investigator to be appropriate candidates for chemotherapy&#xD;
             as current treatment for metastatic breast cancer are excluded. Chemotherapy&#xD;
             administered for adjuvant/neo adjuvant disease is acceptable provided it was&#xD;
             administered at least 1 year prior to study entry.&#xD;
&#xD;
          -  Subjects who received prior treatment or are already receiving everolimus treatment&#xD;
             prior to study entry are not eligible.&#xD;
&#xD;
          -  Subjects with known or history of brain metastases or leptomeningeal disease: subjects&#xD;
             with neurological symptoms must undergo a contrast CT scan or MRI of the brain within&#xD;
             28 days prior to randomization to exclude active brain metastasis. Imaging of the&#xD;
             central nervous system (CNS) is otherwise not required.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bayer Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Bayer</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Yuma</city>
        <state>Arizona</state>
        <zip>85364</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Long Beach</city>
        <state>California</state>
        <zip>90813</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hollywood</city>
        <state>Florida</state>
        <zip>33021</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ashland</city>
        <state>Kentucky</state>
        <zip>41101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Rockville</city>
        <state>Maryland</state>
        <zip>20850</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Pontiac</city>
        <state>Michigan</state>
        <zip>48341</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Newark</city>
        <state>New Jersey</state>
        <zip>07103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jamaica</city>
        <state>New York</state>
        <zip>11432</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Watertown</city>
        <state>South Dakota</state>
        <zip>57201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99208-1129</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Innsbruck</city>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Anderlecht</city>
        <zip>1070</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Edegem</city>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kortrijk</city>
        <zip>8500</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Angers Cedex</city>
        <zip>49055</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nantes</city>
        <zip>44805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>NIMES Cedex 9</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Cloud</city>
        <zip>92210</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tours</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Herne</city>
        <state>Nordrhein-Westfalen</state>
        <zip>44625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Chai Wan</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kowloon</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Afula</city>
        <zip>1834111</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Beer Sheva</city>
        <zip>8410101</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Haifa</city>
        <zip>3109601</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Holon</city>
        <zip>5822012</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jerusalem</city>
        <zip>9103102</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jerusalem</city>
        <zip>9112001</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ramat Gan</city>
        <zip>5262000</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tel Aviv</city>
        <zip>64239</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Zrifin</city>
        <zip>7030000</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bologna</city>
        <state>Emilia-Romagna</state>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Forlì Cesena</city>
        <state>Emilia-Romagna</state>
        <zip>47014</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Modena</city>
        <state>Emilia-Romagna</state>
        <zip>41124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Roma</city>
        <state>Lazio</state>
        <zip>00149</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Roma</city>
        <state>Lazio</state>
        <zip>00161</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Genova</city>
        <state>Liguria</state>
        <zip>16128</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cremona</city>
        <state>Lombardia</state>
        <zip>26100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bari</city>
        <state>Puglia</state>
        <zip>70124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Pisa</city>
        <state>Toscana</state>
        <zip>56126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nagoya</city>
        <state>Aichi</state>
        <zip>464-8681</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sapporo</city>
        <state>Hokkaido</state>
        <zip>060-8648</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Osakasayama</city>
        <state>Osaka</state>
        <zip>589-8511</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hidaka</city>
        <state>Saitama</state>
        <zip>350-1298</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kita-Adachigun</city>
        <state>Saitama</state>
        <zip>362-0806</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Koto-ku</city>
        <state>Tokyo</state>
        <zip>135-8550</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kagoshima</city>
        <zip>892-0833</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Osaka</city>
        <zip>540-0006</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Suwon-si</city>
        <state>Gyeonggido</state>
        <zip>442-723</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Seoul</city>
        <state>Seoul Teugbyeolsi</state>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Busan</city>
        <zip>49241</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Daegu</city>
        <zip>42601</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Incheon</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bialystok</city>
        <zip>15-027</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gdansk</city>
        <zip>80-952</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gdynia</city>
        <zip>81-519</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Poznan</city>
        <zip>61-485</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Warszawa</city>
        <zip>02-781</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Singapore</city>
        <zip>119074</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Singapore</city>
        <zip>169610</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Singapore</city>
        <zip>258499</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Palma de Mallorca</city>
        <state>Illes Baleares</state>
        <zip>07120</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Barcelona</city>
        <zip>08041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madrid</city>
        <zip>28033</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madrid</city>
        <zip>28050</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Pamplona</city>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sevilla</city>
        <zip>41071</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Aarau</city>
        <state>Aargau</state>
        <zip>5001</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kaoshiung</city>
        <zip>81346</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Taichung</city>
        <zip>40705</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Truro</city>
        <state>Cornwall</state>
        <zip>TR1 3LJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Plymouth</city>
        <state>Devon</state>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nottingham</city>
        <state>Nottinghamshire</state>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Taunton</city>
        <state>Somerset</state>
        <zip>TA1 5DA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bristol</city>
        <zip>BS2 8ED</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Merseyside</city>
        <zip>CH63 4JY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Belgium</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hong Kong</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Korea, Republic of</country>
    <country>Norway</country>
    <country>Poland</country>
    <country>Singapore</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>Taiwan</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Canada</country>
    <country>China</country>
    <country>Czech Republic</country>
    <country>Czechia</country>
    <country>Netherlands</country>
  </removed_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 7, 2014</study_first_posted>
  <results_first_submitted>January 17, 2022</results_first_submitted>
  <results_first_submitted_qc>March 9, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 10, 2022</results_first_posted>
  <last_update_submitted>July 25, 2023</last_update_submitted>
  <last_update_submitted_qc>July 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Breast Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Exemestane</mesh_term>
    <mesh_term>Radium Ra 223 dichloride</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 4, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/51/NCT02258451/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 24, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/51/NCT02258451/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study was conducted at 92 centers in 17 countries with first participant first visit on 04-JUN-2015 and primary completion on 22-JAN-2020. The study is still ongoing.</recruitment_details>
      <pre_assignment_details>Overall, 389 participants were screened and 283 were assigned to treatment. Of these, 142 in the radium 223 dichloride arm and 141 in the placebo arm.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Radium-223 + EXE/EVE</title>
          <description>Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
        </group>
        <group group_id="P2">
          <title>Placebo + EXE/EVE</title>
          <description>Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="142"/>
                <participants group_id="P2" count="141"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="142"/>
                <participants group_id="P2" count="141"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Discontinuation all treatment due to progressive disease - radiological progression</title>
              <participants_list>
                <participants group_id="P1" count="88"/>
                <participants group_id="P2" count="95"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Discontinuation all treatment due to progressive disease - clinical progression</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Discontinuation all treatment due to adverse event not associated with clinical disease progression</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Discontinuation all treatment due to adverse event associated with clinical disease progression</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Discontinuation all treatment due to TS-1 started</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Discontinuation all treatment due to event point reached</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Never treated</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Ongoing with any Treatment of radium 223 or placebo, exemestane, or everolimus</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intent-to-Treat Analysis Set (ITT analysis set): included all randomized subjects</population>
      <group_list>
        <group group_id="B1">
          <title>Radium-223 + EXE/EVE</title>
          <description>Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
        </group>
        <group group_id="B2">
          <title>Placebo + EXE/EVE</title>
          <description>Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="142"/>
            <count group_id="B2" value="141"/>
            <count group_id="B3" value="283"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.95" spread="10.40"/>
                    <measurement group_id="B2" value="59.08" spread="11.64"/>
                    <measurement group_id="B3" value="59.52" spread="11.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="142"/>
                    <measurement group_id="B2" value="141"/>
                    <measurement group_id="B3" value="283"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="127"/>
                    <measurement group_id="B2" value="125"/>
                    <measurement group_id="B3" value="252"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Symptomatic Skeletal Event-free Survival (SSE-FS)</title>
        <description>Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause</description>
        <time_frame>Up to 55 months</time_frame>
        <population>ITT analysis set: included all randomized subjects.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Symptomatic Skeletal Event-free Survival (SSE-FS)</title>
          <description>Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause</description>
          <population>ITT analysis set: included all randomized subjects.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="142"/>
                <count group_id="O2" value="141"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.1" lower_limit="17.1" upper_limit="23.6"/>
                    <measurement group_id="O2" value="19.9" lower_limit="16.2" upper_limit="24.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The 1-sided null hypothesis that treatment with radium-223 dichloride does not result in superior SSE-FS to treatment with placebo in subject population was tested against the 1-sided alternative hypothesis that the treatment with radium-223 dichloride results in superior SSE-FS time to treatment the placebo.&#xD;
H0: SSE-FSRadium-223+Exemestane/Everolimus &lt;= SSE-FS Placebo+Exemestane/Everolimus, versus HA: SSE-FSRadium-223+Exemestane/Everolimus &gt; SSE-FS Placebo+Exemestane/Everolimus</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4843</p_value>
            <p_value_desc>1-sided SSE-FS hypotheses were tested using a log-rank test with a 2-sided alpha of 0.2, stratified by the randomization stratification factors.</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.891</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.720</ci_lower_limit>
            <ci_upper_limit>1.102</ci_upper_limit>
            <estimate_desc>The hazard ratio (radium-223 dichloride / placebo) for SSE-FS was calculated using Cox Proportional Hazards Model, stratified by the same stratification factors as randomization.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>The time from the date of randomization to the date of death due to any cause.</description>
        <time_frame>Up to 55 months</time_frame>
        <population>Intent to treat analysis set: all randomized participants</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>The time from the date of randomization to the date of death due to any cause.</description>
          <population>Intent to treat analysis set: all randomized participants</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="142"/>
                <count group_id="O2" value="141"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.0" lower_limit="23.0" upper_limit="31.4"/>
                    <measurement group_id="O2" value="26.4" lower_limit="21.7" upper_limit="28.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.8438</p_value>
            <p_value_desc>P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.968</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.697</ci_lower_limit>
            <ci_upper_limit>1.343</ci_upper_limit>
            <estimate_desc>The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Opiate Use for Cancer Pain</title>
        <description>Interval from the date of randomization to the date of opiate use</description>
        <time_frame>Up to 55 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Opiate Use for Cancer Pain</title>
          <description>Interval from the date of randomization to the date of opiate use</description>
          <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="139"/>
                <count group_id="O2" value="139"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.4" lower_limit="13.2" upper_limit="NA">N/A = Value cannot be estimated due to censored data. Insufficient number of participants with events.</measurement>
                    <measurement group_id="O2" value="18.4" lower_limit="8.3" upper_limit="NA">N/A = Value cannot be estimated due to censored data. Insufficient number of participants with events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.8811</p_value>
            <p_value_desc>P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.962</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.577</ci_lower_limit>
            <ci_upper_limit>1.604</ci_upper_limit>
            <estimate_desc>The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Pain Progression</title>
        <description>Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF &quot;Worst pain in 24 hours&quot; score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.</description>
        <time_frame>Up to 55 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Pain Progression</title>
          <description>Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF &quot;Worst pain in 24 hours&quot; score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.</description>
          <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="139"/>
                <count group_id="O2" value="139"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.6" lower_limit="6.2" upper_limit="13.2"/>
                    <measurement group_id="O2" value="5.7" lower_limit="4.9" upper_limit="8.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Participants with baseline WPS &gt; 8 were included in the analysis population but censored at Day 1.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.6537</p_value>
            <p_value_desc>P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.928</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.667</ci_lower_limit>
            <ci_upper_limit>1.289</ci_upper_limit>
            <estimate_desc>The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Cytotoxic Chemotherapy</title>
        <description>Time from the date of randomization to the date of the first cytotoxic chemotherapy</description>
        <time_frame>Up to 55 months</time_frame>
        <population>ITT analysis set: included all randomized subjects.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Cytotoxic Chemotherapy</title>
          <description>Time from the date of randomization to the date of the first cytotoxic chemotherapy</description>
          <population>ITT analysis set: included all randomized subjects.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="142"/>
                <count group_id="O2" value="141"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.7" lower_limit="9.9" upper_limit="15.8"/>
                    <measurement group_id="O2" value="11.6" lower_limit="9.0" upper_limit="16.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4496</p_value>
            <p_value_desc>P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.884</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.641</ci_lower_limit>
            <ci_upper_limit>1.219</ci_upper_limit>
            <estimate_desc>The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Radiological Progression-free Survival (rPFS)</title>
        <description>Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression).&#xD;
Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.</description>
        <time_frame>Up to 55 months</time_frame>
        <population>ITT analysis set: included all randomized subjects.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Radiological Progression-free Survival (rPFS)</title>
          <description>Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression).&#xD;
Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.</description>
          <population>ITT analysis set: included all randomized subjects.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="142"/>
                <count group_id="O2" value="141"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.9" lower_limit="6.2" upper_limit="9.7"/>
                    <measurement group_id="O2" value="6.7" lower_limit="5.4" upper_limit="8.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3467</p_value>
            <p_value_desc>P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.874</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.660</ci_lower_limit>
            <ci_upper_limit>1.157</ci_upper_limit>
            <estimate_desc>The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Pain Improvement</title>
        <description>In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.</description>
        <time_frame>Up to 55 months</time_frame>
        <population>Safety analysis set with baseline WPS &gt;= 2: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo exemestane, or everolimus), and who in addition had baseline BPI-SF WPS &gt;= 2. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Pain Improvement</title>
          <description>In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.</description>
          <population>Safety analysis set with baseline WPS &gt;= 2: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo exemestane, or everolimus), and who in addition had baseline BPI-SF WPS &gt;= 2. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="91"/>
                <count group_id="O2" value="96"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.5" lower_limit="28.4" upper_limit="49.2"/>
                    <measurement group_id="O2" value="34.4" lower_limit="25.0" upper_limit="44.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.556</p_value>
            <p_value_desc>P-value was calculated using a 2-sided Cochran-Mantel-Haenszel test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.</p_value_desc>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Risk Difference (RD)</param_type>
            <param_value>4.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-10.2</ci_lower_limit>
            <ci_upper_limit>18.4</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)</title>
        <description>An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention.</description>
        <time_frame>From first dosing up to 30 days after the last administration of study treatments, up to 93 months</time_frame>
        <posting_date>10/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Post-treatment Chemotherapy Related Adverse Events</title>
        <time_frame>From post-treatment till end of study, up to 93 months</time_frame>
        <posting_date>10/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Hematological Oxicities: Worst Grade Under Treatment</title>
        <time_frame>From first dosing up to 30 days after the last administration of study treatments, up to 93 months</time_frame>
        <posting_date>10/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With New Primary Malignancies</title>
        <time_frame>From first dosing till end of study, up to 93 months</time_frame>
        <posting_date>10/2023</posting_date>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)</title>
        <description>An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.</description>
        <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)</title>
          <description>An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.</description>
          <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="139"/>
                <count group_id="O2" value="139"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="139"/>
                    <measurement group_id="O2" value="136"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57"/>
                    <measurement group_id="O2" value="53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Radium-223/Placebo-related TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="73"/>
                    <measurement group_id="O2" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exemestane-related TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75"/>
                    <measurement group_id="O2" value="64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Everolimus-related TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="130"/>
                    <measurement group_id="O2" value="125"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Post-treatment Chemotherapy Related Adverse Events</title>
        <time_frame>From post-treatment till primary analysis cutoff date, up to 55 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Post-treatment Chemotherapy Related Adverse Events</title>
          <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="139"/>
                <count group_id="O2" value="139"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>All system organ classes_Any_Grade 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>All system organ classes_Any_Grade 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Blood and lymphatic system disorders_Any_Grade 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Blood and lymphatic system disorders_Febrile neutropenia_Grade 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigations_Any_Grade 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigations_Neutrophil count decreased_Grade 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Hematological Toxicities: Worst Grade Under Treatment</title>
        <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
        <population>Safety analysis set with at least one hematology lab assessment: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Hematological Toxicities: Worst Grade Under Treatment</title>
          <population>Safety analysis set with at least one hematology lab assessment: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="139"/>
                <count group_id="O2" value="137"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Anemia</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="61"/>
                    <measurement group_id="O2" value="57"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="43"/>
                    <measurement group_id="O2" value="55"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leukocytosis</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="139"/>
                    <measurement group_id="O2" value="137"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hemoglobin increased</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="138"/>
                    <measurement group_id="O2" value="137"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lymphocyte count decreased</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                    <measurement group_id="O2" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="63"/>
                    <measurement group_id="O2" value="45"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="43"/>
                    <measurement group_id="O2" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lymphocyte count increased</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="137"/>
                    <measurement group_id="O2" value="135"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neutrophil count decreased</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="47"/>
                    <measurement group_id="O2" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="49"/>
                    <measurement group_id="O2" value="78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Platelet count decreased</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="60"/>
                    <measurement group_id="O2" value="61"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="64"/>
                    <measurement group_id="O2" value="74"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White blood cell decreased</title>
              <category_list>
                <category>
                  <title>Grade 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="37"/>
                    <measurement group_id="O2" value="47"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="59"/>
                    <measurement group_id="O2" value="36"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Normal</title>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                    <measurement group_id="O2" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period</title>
        <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Radium-223 + EXE/EVE</title>
            <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
          </group>
          <group group_id="O2">
            <title>Placebo + EXE/EVE</title>
            <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period</title>
          <population>Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="139"/>
                <count group_id="O2" value="139"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dosing till primary analysis cutoff date, up to 55 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Radium-223 + EXE/EVE</title>
          <description>Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice</description>
        </group>
        <group group_id="E2">
          <title>Placebo + EXE/EVE</title>
          <description>Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (22.1)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="72" subjects_at_risk="139"/>
                <counts group_id="E2" subjects_affected="70" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="61" subjects_at_risk="139"/>
                <counts group_id="E2" subjects_affected="54" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="139"/>
                <counts group_id="E2" events="12" subjects_affected="5" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pericardial effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Colitis ischaemic</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Enteritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Subileus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Injection site extravasation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Sudden death</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Performance status decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>General physical health deterioration</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Multiple organ dysfunction syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hepatic failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hepatic function abnormal</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hepatic haematoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Erysipelas</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Labyrinthitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pseudomembranous colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pyelonephritis acute</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Vestibular neuronitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Febrile infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Biliary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Stoma site infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Biopsy lung</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Haemoglobin decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Influenza A virus test positive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Diabetes mellitus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hypercalcaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="5" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pathological fracture</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="139"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Synovitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Osteonecrosis of jaw</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Malignant pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Metastases to ovary</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Metastases to meninges</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Colon cancer metastatic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Cancer pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dysmetria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Facial paralysis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Paraparesis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Radiculopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Spinal cord compression</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Lumbar radiculopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Neurological decompensation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Hallucination</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hydronephrosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Urinary bladder polyp</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Urinary tract obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="7" subjects_affected="4" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Interstitial lung disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="11" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="139"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="139"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (22.1)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="139" subjects_at_risk="139"/>
                <counts group_id="E2" subjects_affected="135" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="189" subjects_affected="54" subjects_at_risk="139"/>
                <counts group_id="E2" events="142" subjects_affected="40" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="49" subjects_affected="12" subjects_at_risk="139"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="73" subjects_affected="29" subjects_at_risk="139"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="58" subjects_affected="22" subjects_at_risk="139"/>
                <counts group_id="E2" events="19" subjects_affected="9" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="17" subjects_affected="14" subjects_at_risk="139"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="139"/>
                <counts group_id="E2" events="23" subjects_affected="20" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="66" subjects_affected="42" subjects_at_risk="139"/>
                <counts group_id="E2" events="52" subjects_affected="31" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="13" subjects_affected="10" subjects_at_risk="139"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Mouth ulceration</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="139"/>
                <counts group_id="E2" events="19" subjects_affected="10" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="55" subjects_affected="41" subjects_at_risk="139"/>
                <counts group_id="E2" events="41" subjects_affected="30" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="144" subjects_affected="66" subjects_at_risk="139"/>
                <counts group_id="E2" events="165" subjects_affected="69" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="32" subjects_affected="25" subjects_at_risk="139"/>
                <counts group_id="E2" events="31" subjects_affected="22" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="48" subjects_affected="29" subjects_at_risk="139"/>
                <counts group_id="E2" events="49" subjects_affected="25" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="139"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="66" subjects_affected="38" subjects_at_risk="139"/>
                <counts group_id="E2" events="60" subjects_affected="41" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="37" subjects_affected="26" subjects_at_risk="139"/>
                <counts group_id="E2" events="32" subjects_affected="25" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="27" subjects_affected="20" subjects_at_risk="139"/>
                <counts group_id="E2" events="16" subjects_affected="13" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Peripheral swelling</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="139"/>
                <counts group_id="E2" events="16" subjects_affected="9" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="139"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="139"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="22" subjects_affected="15" subjects_at_risk="139"/>
                <counts group_id="E2" events="38" subjects_affected="20" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="16" subjects_affected="12" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="12" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="51" subjects_affected="21" subjects_at_risk="139"/>
                <counts group_id="E2" events="50" subjects_affected="23" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="44" subjects_affected="19" subjects_at_risk="139"/>
                <counts group_id="E2" events="40" subjects_affected="21" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Blood cholesterol increased</sub_title>
                <counts group_id="E1" events="21" subjects_affected="15" subjects_at_risk="139"/>
                <counts group_id="E2" events="22" subjects_affected="10" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="26" subjects_affected="11" subjects_at_risk="139"/>
                <counts group_id="E2" events="21" subjects_affected="9" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="36" subjects_affected="8" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="7" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="43" subjects_affected="14" subjects_at_risk="139"/>
                <counts group_id="E2" events="9" subjects_affected="6" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="42" subjects_affected="12" subjects_at_risk="139"/>
                <counts group_id="E2" events="26" subjects_affected="12" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="37" subjects_affected="28" subjects_at_risk="139"/>
                <counts group_id="E2" events="30" subjects_affected="22" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="43" subjects_affected="13" subjects_at_risk="139"/>
                <counts group_id="E2" events="29" subjects_affected="12" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercholesterolaemia</sub_title>
                <counts group_id="E1" events="28" subjects_affected="12" subjects_at_risk="139"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="36" subjects_affected="17" subjects_at_risk="139"/>
                <counts group_id="E2" events="40" subjects_affected="17" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridaemia</sub_title>
                <counts group_id="E1" events="28" subjects_affected="12" subjects_at_risk="139"/>
                <counts group_id="E2" events="36" subjects_affected="10" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="8" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="29" subjects_affected="19" subjects_at_risk="139"/>
                <counts group_id="E2" events="27" subjects_affected="14" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" events="16" subjects_affected="11" subjects_at_risk="139"/>
                <counts group_id="E2" events="37" subjects_affected="8" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="68" subjects_affected="48" subjects_at_risk="139"/>
                <counts group_id="E2" events="43" subjects_affected="35" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="41" subjects_affected="27" subjects_at_risk="139"/>
                <counts group_id="E2" events="59" subjects_affected="35" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="19" subjects_affected="17" subjects_at_risk="139"/>
                <counts group_id="E2" events="37" subjects_affected="27" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="31" subjects_affected="16" subjects_at_risk="139"/>
                <counts group_id="E2" events="34" subjects_affected="24" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="14" subjects_affected="11" subjects_at_risk="139"/>
                <counts group_id="E2" events="22" subjects_affected="17" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="139"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="28" subjects_affected="21" subjects_at_risk="139"/>
                <counts group_id="E2" events="32" subjects_affected="22" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pathological fracture</sub_title>
                <counts group_id="E1" events="22" subjects_affected="16" subjects_at_risk="139"/>
                <counts group_id="E2" events="22" subjects_affected="15" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="11" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Osteonecrosis of jaw</sub_title>
                <counts group_id="E1" events="12" subjects_affected="9" subjects_at_risk="139"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Spinal pain</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="13" subjects_affected="9" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="139"/>
                <counts group_id="E2" events="12" subjects_affected="9" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="26" subjects_affected="17" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="13" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="35" subjects_affected="25" subjects_at_risk="139"/>
                <counts group_id="E2" events="41" subjects_affected="30" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="12" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="37" subjects_affected="25" subjects_at_risk="139"/>
                <counts group_id="E2" events="37" subjects_affected="26" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="20" subjects_affected="16" subjects_at_risk="139"/>
                <counts group_id="E2" events="23" subjects_affected="17" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="12" subjects_affected="9" subjects_at_risk="139"/>
                <counts group_id="E2" events="15" subjects_affected="14" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="20" subjects_affected="16" subjects_at_risk="139"/>
                <counts group_id="E2" events="19" subjects_affected="16" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="10" subjects_affected="8" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" events="11" subjects_affected="7" subjects_at_risk="139"/>
                <counts group_id="E2" events="31" subjects_affected="9" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="139"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="18" subjects_affected="17" subjects_at_risk="139"/>
                <counts group_id="E2" events="19" subjects_affected="14" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="30" subjects_affected="21" subjects_at_risk="139"/>
                <counts group_id="E2" events="44" subjects_affected="30" subjects_at_risk="139"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="139"/>
                <counts group_id="E2" events="14" subjects_affected="7" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="22" subjects_affected="13" subjects_at_risk="139"/>
                <counts group_id="E2" events="11" subjects_affected="7" subjects_at_risk="139"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Where done for the purpose of filing a patent application, and where deemed necessary, the Sponsor/Bayer may request the PI of the Trial to postpone by 90 days the publication or presentation of a paper. The PI of the Trial may not publish the data yielded by its Site until all the results of the trial (in the case of a multi-center trial) have been published in their entirety or until at least 12 months have passed following completion, discontinuation or early termination of the Trial.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Due to reassessment of the Primary Completion date (PCD) conditions, PCD was moved back to 22 January 2020.&#xD;
Interim survival data on patients transferring from this study to study 16996 (NCT02312960), as of analysis cutoff, was pooled with this study's data to increase the reliability of efficacy results. This pooling was specified in a supplemental SAP dated 24 Jun 2020. All other primary and secondary analysis details were specified in the main study SAP dated 14 Feb 2020.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Therapeutic Area Head</name_or_title>
      <organization>Bayer</organization>
      <phone>(+) 1-888-8422937</phone>
      <email>clinical-trials-contact@bayer.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02258451
org study id: 17096
secondary id: 2014-002114-23
nct id: NCT02258451
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The objective of this study is to assess efficacy and safety of radium 223 dichloride in
      subjects with human epidermal growth factor receptor 2 (HER2) negative hormone receptor
      positive breast cancer with bone metastases treated with exemestane and everolimus

      After implementation of CSP Amendment 10, only a limited number of subjects will remain in
      this study, in order to reduce the burden to study subjects, collection of data will be
      reduced and will focus mainly on acute safety, SSE, and OS. Once subjects are rolled over,
      the long-term safety will be collected and assessed entirely in the separate extended safety
      follow-up study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Symptomatic Skeletal Event-free Survival (SSE-FS)
time frame: Up to 55 months
description: Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause
measure: Overall Survival
time frame: Up to 55 months
description: The time from the date of randomization to the date of death due to any cause.
measure: Time to Opiate Use for Cancer Pain
time frame: Up to 55 months
description: Interval from the date of randomization to the date of opiate use
measure: Time to Pain Progression
time frame: Up to 55 months
description: Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF "Worst pain in 24 hours" score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.
measure: Time to Cytotoxic Chemotherapy
time frame: Up to 55 months
description: Time from the date of randomization to the date of the first cytotoxic chemotherapy
measure: Radiological Progression-free Survival (rPFS)
time frame: Up to 55 months
description: Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression).
Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.
measure: Percentage of Participants With Pain Improvement
time frame: Up to 55 months
description: In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.
measure: Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)
time frame: From first dosing up to 30 days after the last administration of study treatments, up to 93 months
description: An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention.
measure: Number of Participants With Post-treatment Chemotherapy Related Adverse Events
time frame: From post-treatment till end of study, up to 93 months
measure: Number of Participants With Hematological Oxicities: Worst Grade Under Treatment
time frame: From first dosing up to 30 days after the last administration of study treatments, up to 93 months
measure: Number of Participants With New Primary Malignancies
time frame: From first dosing till end of study, up to 93 months
measure: Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)
time frame: From first dosing till primary analysis cutoff date, up to 55 months
description: An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.
measure: Number of Participants With Post-treatment Chemotherapy Related Adverse Events
time frame: From post-treatment till primary analysis cutoff date, up to 55 months
measure: Number of Participants With Hematological Toxicities: Worst Grade Under Treatment
time frame: From first dosing till primary analysis cutoff date, up to 55 months
measure: Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period
time frame: From first dosing till primary analysis cutoff date, up to 55 months
arm group label: Radium-223 dichloride + exemestane/everolimus
arm group type: Experimental
description: Up to 6 cycles of radium-223 dichloride 50kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.
arm group label: Placebo + exemestane/everolimus
arm group type: Placebo Comparator
description: Up to 6 cycles of saline injection (placebo) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.
intervention type: Drug
intervention name: Radium-223 dichloride (Xofigo, BAY88-8223)
description: Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update)
arm group label: Radium-223 dichloride + exemestane/everolimus
intervention type: Drug
intervention name: Placebo (saline)
description: Up to 6 cycles of saline injection
arm group label: Placebo + exemestane/everolimus
intervention type: Drug
intervention name: Exemestane
description: One 25 mg tablet once daily after a meal.
arm group label: Placebo + exemestane/everolimus
arm group label: Radium-223 dichloride + exemestane/everolimus
intervention type: Drug
intervention name: Everolimus
description: The recommended dose of everolimus administered in the study is 10 mg once daily with or without food.
Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.
arm group label: Placebo + exemestane/everolimus
arm group label: Radium-223 dichloride + exemestane/everolimus
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bayer Study Director
role: Study Director
affiliation: Bayer
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country: Austria
country: Belgium
country: France
country: Germany
country: Hong Kong
country: Israel
country: Italy
country: Japan
country: Korea, Republic of
country: Norway
country: Poland
country: Singapore
country: Spain
country: Switzerland
country: Taiwan
country: United Kingdom
country: United States
country: Canada
country: China
country: Czech Republic
country: Czechia
country: Netherlands
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Everolimus
mesh term: Exemestane
mesh term: Radium Ra 223 dichloride
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Due to reassessment of the Primary Completion date (PCD) conditions, PCD was moved back to 22 January 2020.
Interim survival data on patients transferring from this study to study 16996 (NCT02312960), as of analysis cutoff, was pooled with this study's data to increase the reliability of efficacy results. This pooling was specified in a supplemental SAP dated 24 Jun 2020. All other primary and secondary analysis details were specified in the main study SAP dated 14 Feb 2020.
point of contact: 