<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/NCT02258464</url>
  </required_header>
  <id_info>
    <org_study_id>16298</org_study_id>
    <secondary_id>2014-002113-39</secondary_id>
    <nct_id>NCT02258464</nct_id>
  </id_info>
  <brief_title>Study of Radium-223 Dichloride Versus Placebo and Hormonal Treatment as Background Therapy in Subjects With Bone Predominant HER2 (Human Epidermal Growth Factor Receptor 2) Negative Hormone Receptor Positive Metastatic Breast Cancer</brief_title>
  <official_title>A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride Versus Placebo When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases Treated With Hormonal Treatment Background Therapy</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_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study was to assess efficacy and safety of radium-223 dichloride in&#xD;
      subjects with human epidermal growth factor receptor 2 negative (HER2 negative) hormone&#xD;
      receptor positive breast cancer with bone metastases treated with hormonal treatment&#xD;
      background therapy&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Due to lower than expected recruitment since the start of study&#xD;
  </why_stopped>
  <start_date type="Actual">March 2, 2015</start_date>
  <completion_date type="Actual">August 13, 2019</completion_date>
  <primary_completion_date type="Actual">August 13, 2019</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 approximately 51 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 approximately 51 months</time_frame>
    <description>Time from randomization to death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Opiate Use for Cancer Pain</measure>
    <time_frame>Up to approximately 51 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 approximately 51 months</time_frame>
    <description>Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is defined as an increase of 2 or more points in the &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 occurs first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Improvement Rate</measure>
    <time_frame>Up to approximately 51 months</time_frame>
    <description>The percentage of participants (baseline WPS&gt;=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Cytotoxic Chemotherapy</measure>
    <time_frame>Up to approximately 51 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 approximately 51 months</time_frame>
    <description>Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-emergent Adverse Events</measure>
    <time_frame>Up to approximately 7 months</time_frame>
    <description>Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events</measure>
    <time_frame>From 30 days after the last dose of study treatment until the end of study, assessed up to approximately 44 months</time_frame>
    <description>AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">99</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Radium 223 dichloride</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</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 National Institute of Standards and Technology [NIST] update)</description>
    <arm_group_label>Radium 223 dichloride</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</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Background hormonal therapy</intervention_name>
    <description>Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Radium 223 dichloride</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#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;
          -  Women (≥18 years of age) with metastatic breast cancer not amenable to curative&#xD;
             treatment by surgery or radiotherapy.&#xD;
&#xD;
          -  Documentation of menopausal status: post menopausal or premenopausal subjects are&#xD;
             eligible.&#xD;
&#xD;
          -  Subjects with bone dominant disease with at least 2 skeletal metastases identified at&#xD;
             baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI).&#xD;
             Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph&#xD;
             nodes)and/or visceral metastases is allowed.&#xD;
&#xD;
          -  Measurable or non-measurable disease (but radiologically evaluable) according to&#xD;
             Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.&#xD;
&#xD;
          -  Subjects must have received at least one line of hormonal therapy in the metastatic&#xD;
             setting&#xD;
&#xD;
          -  Subjects who are eligible for further standard of care endocrine treatment.&#xD;
&#xD;
          -  Subjects enrolled in the current study must start treatment with the single hormone&#xD;
             agent either within 15 days prior to randomization or after randomization (before or&#xD;
             simultaneously to the first injection of Ra-223/placebo).&#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) tor bone,&#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 bisphosphonate and denosumab. and are required to&#xD;
             have been on such therapy for at least 1 month 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;
          -  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.&#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;
&#xD;
          -  Known presence of osteonecrosis of jaw.&#xD;
&#xD;
          -  Patients with immediately life-threatening visceral disease, for whom chemotherapy is&#xD;
             the preferred treatment option.&#xD;
&#xD;
          -  Lymphangitic carcinomatosis.&#xD;
&#xD;
          -  Patients with ascites requiring paracentesis within 2 weeks prior to study entry&#xD;
             (signature of informed consent) and during the screening period.&#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>Bakersfield</city>
        <state>California</state>
        <zip>93309</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>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cedar Rapids</city>
        <state>Iowa</state>
        <zip>52403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Annapolis</city>
        <state>Maryland</state>
        <zip>21401</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>Pontiac</city>
        <state>Michigan</state>
        <zip>48341</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>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213-3180</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Linz</city>
        <state>Oberösterreich</state>
        <zip>4020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Innsbruck</city>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3E 0V9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 4L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Newmarket</city>
        <state>Ontario</state>
        <zip>L3Y 2P9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ostrava</city>
        <zip>708 52</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Praha 2</city>
        <zip>12808</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Herlev</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Helsinki</city>
        <zip>00290</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tampere</city>
        <zip>FIN-33520</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Angers Cedex</city>
        <zip>49055</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>Tübingen</city>
        <state>Baden-Württemberg</state>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bonn</city>
        <state>Nordrhein-Westfalen</state>
        <zip>53105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Essen</city>
        <state>Nordrhein-Westfalen</state>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kowloon</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cork</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dublin</city>
        <zip>7</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Afula</city>
        <zip>1834111</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>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>Kfar Saba</city>
        <zip>4428164</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>Zerifin</city>
        <zip>7030000</zip>
        <country>Israel</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>03080</zip>
        <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>Seoul</city>
        <zip>120-752</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nieuwegein</city>
        <zip>3435 CM</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Zwolle</city>
        <zip>8025 AB</zip>
        <country>Netherlands</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>Gdynia</city>
        <zip>81-519</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>L'Hospitalet de Llobregat</city>
        <state>Barcelona</state>
        <zip>08907</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>A Coruña</city>
        <zip>15009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Barcelona</city>
        <zip>08025</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>Madrid</city>
        <zip>28033</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madrid</city>
        <zip>28040</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>Málaga</city>
        <zip>29010</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>Zaragoza</city>
        <zip>50009</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>Taipei</city>
        <zip>11217</zip>
        <country>Taiwan</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>Northwood</city>
        <state>Middlesex</state>
        <zip>HA6 2RN</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>Cottingham</city>
        <zip>HU16 5JQ</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>
    <facility>
      <address>
        <city>Sheffield</city>
        <zip>S10 2SJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Canada</country>
    <country>Czechia</country>
    <country>Denmark</country>
    <country>Finland</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hong Kong</country>
    <country>Ireland</country>
    <country>Israel</country>
    <country>Korea, Republic of</country>
    <country>Netherlands</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>China</country>
    <country>Czech Republic</country>
    <country>Italy</country>
    <country>Sweden</country>
  </removed_countries>
  <link>
    <url>http://clinicaltrials.bayer.com/</url>
    <description>Click here to find results for studies related to Bayer products.</description>
  </link>
  <link>
    <url>http://www.clinicaltrialsregister.eu/</url>
    <description>Click here to find information about studies related to Bayer Healthcare products conducted in Europe.</description>
  </link>
  <verification_date>July 2020</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>July 1, 2020</results_first_submitted>
  <results_first_submitted_qc>July 29, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">August 10, 2020</results_first_posted>
  <last_update_submitted>July 29, 2020</last_update_submitted>
  <last_update_submitted_qc>July 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 10, 2020</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>Radium Ra 223 dichloride</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <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>August 12, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT02258464/SAP_000.pdf</document_url>
    </provided_document>
    <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>April 3, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT02258464/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>151 participants were screened at 69 active centers in 20 countries, the first participant first visit was on 02 Mar 2015 and last participant last visit was on 13 Aug 2019</recruitment_details>
      <pre_assignment_details>Of the 151 screened participants, 99 participants (65.6%) completed screening and were assigned to treatment: 49 in the radium 223 dichloride and 50 in the placebo arm</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Radium 223 Dichloride</title>
          <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
                <participants group_id="P2" count="50"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Progressive disease (PD)</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="17"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study drug never administered</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>AE not related to clinical PD</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <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="5"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>AE related to clinical PD</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intend-to-treat (ITT) analysis set: all randomized participants</population>
      <group_list>
        <group group_id="B1">
          <title>Radium 223 Dichloride</title>
          <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</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="49"/>
            <count group_id="B2" value="50"/>
            <count group_id="B3" value="99"/>
          </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="57.08" spread="11.51"/>
                    <measurement group_id="B2" value="58.74" spread="11.97"/>
                    <measurement group_id="B3" value="57.92" spread="11.72"/>
                  </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="49"/>
                    <measurement group_id="B2" value="50"/>
                    <measurement group_id="B3" value="99"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="94"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</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>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</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>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="75"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</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>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </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 approximately 51 months</time_frame>
        <population>Intent to treat analysis set: all randomized participants</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</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>Intent to treat analysis set: all randomized participants</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.1" spread="21.8" lower_limit="21.8" upper_limit="43.0"/>
                    <measurement group_id="O2" value="18.4" spread="9.1" lower_limit="9.1" upper_limit="28.2"/>
                  </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 null hypothesis that both treatment groups have the same SSE-FS distribution will be tested against the alternative hypothesis that the distribution of SSE-FS time in radium-223 dichloride is different from the placebo group</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3339</p_value>
            <p_value_desc>The SSE-FS was compared using a stratified log-rank test with a 2-sided alpha of 0.2</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (Radium 223/Placebo)</param_type>
            <param_value>0.745</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.504</ci_lower_limit>
            <ci_upper_limit>1.102</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Time from randomization to death from any cause</description>
        <time_frame>Up to approximately 51 months</time_frame>
        <population>Intent to treat analysis set: all randomized participants</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Time from randomization to death from any cause</description>
          <population>Intent to treat analysis set: all randomized participants</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.0" lower_limit="22.9" upper_limit="NA">NA: Value not estimated due to censored data</measurement>
                    <measurement group_id="O2" value="32.4" lower_limit="23.7" upper_limit="NA">NA: Value not estimated due to censored data</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>Other</non_inferiority_type>
            <p_value>0.7259</p_value>
            <method>Log Rank</method>
            <param_type>Hazard ratio (Radium 223/Placebo)</param_type>
            <param_value>0.888</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.576</ci_lower_limit>
            <ci_upper_limit>1.370</ci_upper_limit>
          </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 approximately 51 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one study drug administration (radium 223 dichloride or placebo)</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</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 study drug administration (radium 223 dichloride or placebo)</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.3" lower_limit="8.3" upper_limit="NA">NA: Value not estimated due to censored data</measurement>
                    <measurement group_id="O2" value="20.2" lower_limit="8.8" upper_limit="NA">NA: Value not estimated due to censored data</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>Other</non_inferiority_type>
            <p_value>0.8785</p_value>
            <method>Log Rank</method>
            <param_type>Hazard ratio (Radium 223/Placebo)</param_type>
            <param_value>0.932</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.513</ci_lower_limit>
            <ci_upper_limit>1.693</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Pain Progression</title>
        <description>Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is defined as an increase of 2 or more points in the &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 occurs first</description>
        <time_frame>Up to approximately 51 months</time_frame>
        <population>Safety analysis set: all randomized participants who received at least one study drug administration (radium 223 dichloride or placebo)</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Pain Progression</title>
          <description>Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is defined as an increase of 2 or more points in the &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 occurs first</description>
          <population>Safety analysis set: all randomized participants who received at least one study drug administration (radium 223 dichloride or placebo)</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.8" lower_limit="5.9" upper_limit="21.3"/>
                    <measurement group_id="O2" value="8.8" lower_limit="3.7" upper_limit="14.3"/>
                  </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>Other</non_inferiority_type>
            <p_value>0.5240</p_value>
            <method>Log Rank</method>
            <param_type>Hazard ratio (Radium 223/Placebo)</param_type>
            <param_value>0.824</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.556</ci_lower_limit>
            <ci_upper_limit>1.220</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pain Improvement Rate</title>
        <description>The percentage of participants (baseline WPS&gt;=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart</description>
        <time_frame>Up to approximately 51 months</time_frame>
        <population>Participants in safety analysis set taken into account for this endpoint analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Pain Improvement Rate</title>
          <description>The percentage of participants (baseline WPS&gt;=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart</description>
          <population>Participants in safety analysis set taken into account for this endpoint analysis</population>
          <units>percentage of participants analyzed</units>
          <param>Number</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="35"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.5" spread="25.9" lower_limit="25.9" upper_limit="50.4"/>
                    <measurement group_id="O2" value="25.7" spread="16.2" lower_limit="16.2" upper_limit="37.5"/>
                  </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>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.345</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Difference (Radium 223 - Placebo) %</param_type>
            <param_value>11.8</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.7</ci_lower_limit>
            <ci_upper_limit>26.3</ci_upper_limit>
          </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 approximately 51 months</time_frame>
        <population>Intent to treat analysis set: all randomized participants</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</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>Intent to treat analysis set: all randomized participants</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.0" spread="14.1" lower_limit="14.1" upper_limit="22.4"/>
                    <measurement group_id="O2" value="17.3" spread="10.9" lower_limit="10.9" upper_limit="27.6"/>
                  </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>Other</non_inferiority_type>
            <p_value>0.9128</p_value>
            <method>Log Rank</method>
            <param_type>Hazard ratio (Radium 223/Placebo)</param_type>
            <param_value>0.968</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.657</ci_lower_limit>
            <ci_upper_limit>1.425</ci_upper_limit>
          </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 first radiological progression or death (if death occurs before progression)</description>
        <time_frame>Up to approximately 51 months</time_frame>
        <population>Intent to treat analysis set: all randomized participants</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Radiological Progression-free Survival (rPFS)</title>
          <description>Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)</description>
          <population>Intent to treat analysis set: all randomized participants</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>80% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.1" spread="5.7" lower_limit="5.7" upper_limit="10.6"/>
                    <measurement group_id="O2" value="5.8" spread="5.1" lower_limit="5.1" upper_limit="7.9"/>
                  </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>Other</non_inferiority_type>
            <p_value>0.9227</p_value>
            <method>Log Rank</method>
            <param_type>Hazard ratio (Radium 223/Placebo)</param_type>
            <param_value>1.023</param_value>
            <ci_percent>80</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.753</ci_lower_limit>
            <ci_upper_limit>1.391</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-emergent Adverse Events</title>
        <description>Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake</description>
        <time_frame>Up to approximately 7 months</time_frame>
        <population>Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-emergent Adverse Events</title>
          <description>Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake</description>
          <population>Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)</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="48"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46"/>
                    <measurement group_id="O2" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Radium 223/Placebo related TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events</title>
        <description>AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event</description>
        <time_frame>From 30 days after the last dose of study treatment until the end of study, assessed up to approximately 44 months</time_frame>
        <population>Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)</population>
        <group_list>
          <group group_id="O1">
            <title>Radium 223 Dichloride</title>
            <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events</title>
          <description>AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event</description>
          <population>Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)</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="48"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any post-treatment AE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anaemia</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>Febrile neutropenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chest pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fibula fracture</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rib fracture</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tibia fracture</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Traumatic fracture</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Weight decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Arthralgia</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>Back pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bone pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Muscle spasms</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>Musculoskeletal chest pain</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>Osteonecrosis of jaw</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>Pain in extremity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pathological fracture</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Spinal pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cauda equina syndrome</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Paraesthesia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Spinal cord compression</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Acute kidney injury</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the start of study drug administration until the end of study, assessed up to approximately 51 months</time_frame>
      <desc>Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event</desc>
      <group_list>
        <group group_id="E1">
          <title>Radium 223 Dichloride</title>
          <description>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (22.0)</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="18" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="49"/>
              </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="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Oesophagitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacteraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fibula fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Tibia fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pathological fracture</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Cancer pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Nerve compression</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Psychotic disorder</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (22.0)</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="43" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="44" subjects_at_risk="49"/>
              </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="5" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="7" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="5" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="48"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="15" subjects_affected="10" subjects_at_risk="48"/>
                <counts group_id="E2" events="10" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="18" subjects_affected="12" subjects_at_risk="48"/>
                <counts group_id="E2" events="13" subjects_affected="9" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="48"/>
                <counts group_id="E2" events="11" subjects_affected="7" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="15" subjects_affected="12" subjects_at_risk="48"/>
                <counts group_id="E2" events="10" subjects_affected="9" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Traumatic fracture</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="49"/>
              </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="14" subjects_affected="10" subjects_at_risk="48"/>
                <counts group_id="E2" events="17" subjects_affected="11" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="18" subjects_affected="14" subjects_at_risk="48"/>
                <counts group_id="E2" events="10" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="12" subjects_affected="11" subjects_at_risk="48"/>
                <counts group_id="E2" events="15" subjects_affected="9" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="10" subjects_affected="6" subjects_at_risk="48"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="48"/>
                <counts group_id="E2" events="9" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pathological fracture</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="48"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Spinal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="7" subjects_affected="4" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="19" subjects_affected="13" subjects_at_risk="48"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="49"/>
              </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="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hot flush</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Due to the premature enrollment discontinuation, reduced sample size, and potentially curtailed active follow up, the planned number of SSE FS events was not achieved, limiting the assessment of the primary efficacy endpoint.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Therapeutic Area Head</name_or_title>
      <organization>Bayer AG</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/NCT02258464
org study id: 16298
secondary id: 2014-002113-39
nct id: NCT02258464
lead sponsor: 
has dmc: Yes
is fda regulated device: No
The objective of this study was to assess efficacy and safety of radium-223 dichloride in
      subjects with human epidermal growth factor receptor 2 negative (HER2 negative) hormone
      receptor positive breast cancer with bone metastases treated with hormonal treatment
      background therapy
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 approximately 51 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 approximately 51 months
description: Time from randomization to death from any cause
measure: Time to Opiate Use for Cancer Pain
time frame: Up to approximately 51 months
description: Interval from the date of randomization to the date of opiate use
measure: Time to Pain Progression
time frame: Up to approximately 51 months
description: Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is defined as an increase of 2 or more points in the "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 occurs first
measure: Pain Improvement Rate
time frame: Up to approximately 51 months
description: The percentage of participants (baseline WPS>=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart
measure: Time to Cytotoxic Chemotherapy
time frame: Up to approximately 51 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 approximately 51 months
description: Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)
measure: Number of Participants With Treatment-emergent Adverse Events
time frame: Up to approximately 7 months
description: Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake
measure: Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events
time frame: From 30 days after the last dose of study treatment until the end of study, assessed up to approximately 44 months
description: AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event
arm group label: Radium 223 dichloride
arm group type: Experimental
description: Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks
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 National Institute of Standards and Technology [NIST] update)
arm group label: Radium 223 dichloride
intervention type: Drug
intervention name: Placebo (saline)
description: Up to 6 cycles of saline injection
arm group label: Placebo
intervention type: Other
intervention name: Background hormonal therapy
description: Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.
arm group label: Placebo
arm group label: Radium 223 dichloride
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: Canada
country: Czechia
country: Denmark
country: Finland
country: France
country: Germany
country: Hong Kong
country: Ireland
country: Israel
country: Korea, Republic of
country: Netherlands
country: Norway
country: Poland
country: Singapore
country: Spain
country: Switzerland
country: Taiwan
country: United Kingdom
country: United States
country: China
country: Czech Republic
country: Italy
country: Sweden
url: http://clinicaltrials.bayer.com/
description: Click here to find results for studies related to Bayer products.
url: http://www.clinicaltrialsregister.eu/
description: Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Radium Ra 223 dichloride
provided document: 
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reported events: 
certain agreements: 
limitations and caveats: Due to the premature enrollment discontinuation, reduced sample size, and potentially curtailed active follow up, the planned number of SSE FS events was not achieved, limiting the assessment of the primary efficacy endpoint.
point of contact: 