<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/NCT01718353</url>
  </required_header>
  <id_info>
    <org_study_id>CABAZL06056</org_study_id>
    <secondary_id>U1111-1130-9893</secondary_id>
    <nct_id>NCT01718353</nct_id>
  </id_info>
  <brief_title>Early Switch From First-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the Opposite Sequence, Exploring Molecular Markers in Men With Metastatic Castration-Resistant Prostate Cancer (mCRPC)</brief_title>
  <acronym>TAXYNERGY</acronym>
  <official_title>Phase II Trial to Evaluate Benefit of Early Switch From First-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the Opposite Sequence, Exploring Molecular Markers and Mechanisms of Taxane Resistance in Men With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Have Not Received Prior Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sanofi</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Docetaxel and cabazitaxel are cancer chemotherapy agents of the taxane drug class. The&#xD;
      purpose of this study is to explore the benefit, for treatment of metastatic&#xD;
      castration-resistant prostate cancer (mCRPC), of a regimen in which participants begin&#xD;
      treatment with either of these two taxane drugs (docetaxel or cabazitaxel, in combination&#xD;
      with prednisone) and are switched to the other taxane drug if prostate-specific antigen (PSA)&#xD;
      value does not decrease ≥30% after 4 cycles. As defined in study protocol amendment 3,&#xD;
      efficacy results are summarized for all participants combined, irrespective of which agent&#xD;
      (docetaxel or cabazitaxel) was administered initially, rather than separately for the two&#xD;
      groups based on taxane administered initially. One of the primary outcome measures is&#xD;
      percentage of participants with a ≥50% sustained decrease from baseline in PSA at any time&#xD;
      during the trial. By providing an opportunity for patients to switch taxane based on early&#xD;
      PSA response, there may be a difference in result for this measure versus result in a study&#xD;
      where it was not possible to switch. The other primary outcome measures are change from&#xD;
      baseline in circulating tumor cells (CTCs) biomarkers percent androgen receptor nuclear&#xD;
      localization (%ARNL) and microtubule bundling (MTB).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  Participants were treated until progressive disease, unacceptable toxicity, death, or&#xD;
           participant's refusal of further study treatment. All participants were followed until&#xD;
           death or the study cut-off date, whichever came first.&#xD;
&#xD;
        -  Study cut-off was 1 month after the last participant last treatment.&#xD;
&#xD;
        -  Participants alive at the cut-off date were not followed for overall survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2013</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants With PSA Response</measure>
    <time_frame>Baseline, Pre-dose every 3 weeks, 30 days after last treatment administration (End of treatment [EOT]), every 3 months (for 1 year) then every 6 months until PSA progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
    <description>PSA response was defined as ≥50% decrease in PSA levels in both treatment arms from baseline, during the whole treatment, before treatment switch and after treatment switch. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart). Because the purpose of this study is to explore the benefit of a regimen in which participants are switched to a different taxane if PSA does not decrease ≥30% after 4 cycles, irrespective of which agent (docetaxel or cabazitaxel) is administered initially, the data for participants who began treatment with docetaxel and for those who began treatment with cabazitaxel were combined for the efficacy analyses.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Drug-target Engagement in Circulating Tumor Cells (CTCs): Change From Baseline at Cycle 1 Day 8 in Percent Androgen Receptor Nuclear Localization (%ARNL) by Categories of PSA Decrease From Baseline (≥50%, Not ≥50%) After Cycle 4</measure>
    <time_frame>Baseline and Cycle 1 Day 8, Cycle 4</time_frame>
    <description>Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained androgen receptor (AR) nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced microtubule bundling (MTB). Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. %ARNL was assessed by quantitative analysis of images of CTCs captured by geometrically enhanced differential immunocapture (GEDI). Reduction from baseline in %ARNL (percentage of total cellular AR that is located in the nucleus) may indicate inhibition of AR signaling. Change from baseline in %ARNL at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥50%, Not ≥50%) after Cycle 4.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Drug-target Engagement in CTCs: Change From Baseline at Cycle 1 Day 8 in MTB by Categories of PSA Decrease From Baseline (≥30%, Not ≥30%) After Cycle 4</measure>
    <time_frame>Baseline and Cycle 1 Day 8, Cycle 4</time_frame>
    <description>Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained AR nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced MTB. Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. MTB in images of CTCs captured by GEDI was qualitatively assessed by three independent operators for increase compared with baseline on a scale of 0 to 3 from no to most MTB increase. Increase from baseline in MTB may indicate inhibition of AR signaling. Change from baseline in MTB at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥30%, Not ≥30%) after Cycle 4.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>From Baseline until DP or death due to any cause or study cut off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
    <description>PFS was defined as the time interval between the date of random allocation of the treatment and the date of first documentation of any of the following: radiographic tumor progression (using Modified Response Evaluation Criteria in Solid Tumors [RECIST1.1] before any switch and during the study), clinical progression (including skeletal-related events, increasing pain requiring escalation of narcotic analgesics, urinary obstruction), PSA progression or death from any cause. Analysis was performed by Kaplan Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSA Progression Free Survival</measure>
    <time_frame>From Baseline until DP or death due to any cause or study cut off date, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
    <description>PSA progression-free survival before any switch and PSA progression free survival during the study was defined as the time interval between the date of Day 1 of Cycle 1 to the date of either first PSA progression or death due to any cause whichever came first. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Objective Response</measure>
    <time_frame>From baseline until DP or study cut off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiographic Progression-free Survival (rPFS)</measure>
    <time_frame>From baseline, every 12 weeks until radiological tumor progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Progression-free Survival (cPFS)</measure>
    <time_frame>Baseline, Pre-dose every 3 weeks, EOT, every 3 months (for 1 year) until first SRE occurrence or death or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
    <description>cPFS was assessed before switch and during the study including skeletal-related events (SRE), increasing pain requiring escalation of narcotic analgesics, urinary obstruction, etc. SRE included pathological fractures and/or spinal cord compression, need for bone irradiation (including radioisotopes or bone surgery), change of antineoplastic therapy (including introduction of bisphosphonates or denosumab in the face of increase in pain) to treat bone pain. Pain was assessed using present pain intensity (PPI) scale (0=no pain, up to 5=excruciating pain) and analgesics used for cancer pain (1 point for non-narcotic medications and 4 points for narcotic medications).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>From baseline until death due to any cause or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
    <description>Overall survival before switch and overall survival during the study was defined as the time interval from the date of random allocation to the date of death due to any cause until study cut-off date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With ≥30% and ≥50% Reduction in PSA Response</measure>
    <time_frame>From baseline until DP or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
    <description>Participants with ≥30% and ≥50% reduction in PSA response from base line were evaluated in participants who were previously treated with a high potency androgen receptor (AR)-targeted agent (AR signaling inhibitor or cytochrome P450 17 alphahydroxylase/17,20lyase [CYP 17] inhibitor).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">63</enrollment>
  <condition>Prostate Cancer Metastatic</condition>
  <arm_group>
    <arm_group_label>Docetaxel + Prednisone (Treatment A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Docetaxel 75 mg/m^2 intravenous (IV) infusion on Day 1 of Cycle 1 and every 3 weeks (q3w) thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4 switched to Cabazitaxel 25mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until disease progression (DP), death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cabazitaxel + Prednisone (Treatment B)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4 switched to Docetaxel 75mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DOCETAXEL (XRP6976)</intervention_name>
    <description>Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous</description>
    <arm_group_label>Docetaxel + Prednisone (Treatment A)</arm_group_label>
    <other_name>Taxotere®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CABAZITAXEL (XRP6258)</intervention_name>
    <description>Pharmaceutical form: Concentrate and solvent for solution for infusion Route of administration: Intravenous</description>
    <arm_group_label>Cabazitaxel + Prednisone (Treatment B)</arm_group_label>
    <other_name>Jevtana®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Pharmaceutical form: Tablet Route of administration: Oral</description>
    <arm_group_label>Cabazitaxel + Prednisone (Treatment B)</arm_group_label>
    <arm_group_label>Docetaxel + Prednisone (Treatment A)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria :&#xD;
&#xD;
          -  Histologically- or cytologically-confirmed prostate adenocarcinoma with documented&#xD;
             distant metastases (M1 disease).&#xD;
&#xD;
          -  Progressive disease while receiving hormonal therapy or after surgical castration.&#xD;
&#xD;
          -  Effective castration (serum testosterone levels ≤50 ng/dL) by orchiectomy and/or&#xD;
             luteinizing hormone releasing hormone agonists or antagonist with or without&#xD;
             anti-androgens.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Prior chemotherapy for prostate cancer, except estramustine and adjuvant/neoadjuvant&#xD;
             treatment completed &gt;3 years ago. Prior treatment with sipuleucel-T immunotherapy was&#xD;
             allowed at the condition participant did not receive prior chemotherapy.&#xD;
&#xD;
          -  Less than 28 days elapsed from prior treatment with estramustine, radiotherapy or&#xD;
             surgery to the time of random allocation.&#xD;
&#xD;
          -  Prior beta isotope therapy, whole pelvic radiotherapy, or radiotherapy to &gt;30% of bone&#xD;
             marrow.&#xD;
&#xD;
          -  Adverse events (excluding alopecia and those listed in the specific exclusion&#xD;
             criteria) from any prior anticancer therapy of grade &gt;1(National Cancer Institute&#xD;
             Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03) at the time of&#xD;
             random allocation.&#xD;
&#xD;
          -  Less than 18 years of age.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status &gt;2.&#xD;
&#xD;
          -  History of brain metastases, uncontrolled spinal cord compression, or carcinomatous&#xD;
             meningitis or new evidence of brain or leptomeningeal disease.&#xD;
&#xD;
          -  Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial&#xD;
             (pTis, pTa and pT1) bladder cancer were allowed, as well as any other cancer for which&#xD;
             chemotherapy had been completed ≥3 years ago and from which the participant had been&#xD;
             disease-free for ≥3 years.&#xD;
&#xD;
          -  Participation in another clinical trial and any concurrent treatment with any&#xD;
             investigational drug within 30 days prior to random allocation.&#xD;
&#xD;
          -  Any of the following within 6 months prior to study enrollment: myocardial infarction,&#xD;
             severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York&#xD;
             Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient&#xD;
             ischemic attack.&#xD;
&#xD;
          -  Any of the following within 3 months prior to random allocation: treatment resistant&#xD;
             peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory&#xD;
             bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled&#xD;
             thromboembolic event.&#xD;
&#xD;
          -  Acquired immunodeficiency syndrome (AIDS)-related illnesses or known HIV disease&#xD;
             requiring antiretroviral treatment.&#xD;
&#xD;
          -  Any severe acute or chronic medical condition which could impair the ability of the&#xD;
             participant to participate in to the study or interfere with interpretation of study&#xD;
             results, or participant unable to comply with the study procedures.&#xD;
&#xD;
          -  Concomitant treatment with biphosphonates or denosumab except if the dose had been&#xD;
             stable for 4 weeks prior to enrollment.&#xD;
&#xD;
          -  Absence of signed and dated Institutional Review Board (IRB)-approved participant&#xD;
             informed consent prior to enrollment into the study.&#xD;
&#xD;
          -  Participants with reproductive potential who did not agree to use an accepted and&#xD;
             effective method of contraception during the study treatment period. The definition of&#xD;
             &quot;effective method of contraception&quot; was based on the investigator's judgment.&#xD;
&#xD;
          -  History of hypersensitivity to docetaxel or polysorbate 80.&#xD;
&#xD;
          -  Inadequate organ and bone marrow function.&#xD;
&#xD;
          -  Contraindications to the use of corticosteroid treatment.&#xD;
&#xD;
          -  Symptomatic peripheral neuropathy grade &gt;2 (NCI CTCAE v.4.03).&#xD;
&#xD;
          -  Treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a&#xD;
             two-week wash-out period was necessary for participants who were already on these&#xD;
             treatments).&#xD;
&#xD;
        The above information was not intended to contain all considerations relevant to a&#xD;
        participant's potential participation in a clinical trial.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Sciences &amp; Operations</last_name>
    <role>Study Director</role>
    <affiliation>Sanofi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Investigational Site Number 840003</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294-3300</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840102</name>
      <address>
        <city>Washington, D.C.</city>
        <state>District of Columbia</state>
        <zip>20016-2695</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840005</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840025</name>
      <address>
        <city>Metairie</city>
        <state>Louisiana</state>
        <zip>70006</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840002</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840007</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840017</name>
      <address>
        <city>Rockville</city>
        <state>Maryland</state>
        <zip>20850</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840010</name>
      <address>
        <city>Cherry Hill</city>
        <state>New Jersey</state>
        <zip>08003</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840015</name>
      <address>
        <city>East Orange</city>
        <state>New Jersey</state>
        <zip>07018</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840001</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840013</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029-6574</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840009</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29414</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840012</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 840004</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 124001</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 124004</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2L 4M1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 124002</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2W1S6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 124006</name>
      <address>
        <city>Québec</city>
        <state>Quebec</state>
        <zip>G1R 2J6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 124005</name>
      <address>
        <city>Sherbrooke</city>
        <state>Quebec</state>
        <zip>J1H 5N4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>October 29, 2012</study_first_submitted>
  <study_first_submitted_qc>October 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 31, 2012</study_first_posted>
  <results_first_submitted>August 5, 2016</results_first_submitted>
  <results_first_submitted_qc>October 11, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">November 20, 2017</results_first_posted>
  <last_update_submitted>October 11, 2017</last_update_submitted>
  <last_update_submitted_qc>October 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 20, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study was conducted at 19 centers in Canada and United States. A total of 81 participants were screened between 20 March 2013 and 29 May 2014, of which, 63 participants were randomized and 61 were treated. A total of 18 participants were screen failure mainly due to exclusion criteria met and inclusion criteria not met.</recruitment_details>
      <pre_assignment_details>Participants were randomized by Interactive Voice Response System (IVRS) in 2:1 ratio (Treatment A : Treatment B) to receive either Treatment A (Docetaxel + Prednisone) or Treatment B (Cabazitaxel + Prednisone).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Docetaxel + Prednisone (Treatment A)</title>
          <description>Docetaxel 75 mg/m^2 intravenous (IV) infusion on Day 1 of Cycle 1 and every 3 weeks (q3w) thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% prostate-specific antigen (PSA) reduction from baseline at the end of Cycle 4 switched to Cabazitaxel 25mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until disease progression (DP), death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
        </group>
        <group group_id="P2">
          <title>Cabazitaxel + Prednisone (Treatment B)</title>
          <description>Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4 switched to Docetaxel 75mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated up to End of Cycle 4</title>
              <participants_list>
                <participants group_id="P1" count="32">7 participants discontinued before Cycle 5</participants>
                <participants group_id="P2" count="16">6 participants discontinued before Cycle 5</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated From Cycle 5</title>
              <participants_list>
                <participants group_id="P1" count="23">12 participants switched from Treatment A to B &amp; 3 participants switched from Treatment B to A.</participants>
                <participants group_id="P2" count="25">3 participants switched from Treatment B to A &amp; 12 participants switched from Treatment A to B.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="29">Participants at study cut-off, Adverse Event (AE), DP &amp; consent withdrawn were considered completed.</participants>
                <participants group_id="P2" count="17">Participants at study cut-off, AE, DP and consent withdrawn were considered completed.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Principal Investigator's Decision</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Randomized but not treated</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Docetaxel + Prednisone (Treatment A)</title>
          <description>Docetaxel 75 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4 switched to Cabazitaxel 25mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
        </group>
        <group group_id="B2">
          <title>Cabazitaxel + Prednisone (Treatment B)</title>
          <description>Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4 switched to Docetaxel 75mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</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="41"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="63"/>
          </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="69.9" spread="7.8"/>
                    <measurement group_id="B2" value="69.2" spread="9.5"/>
                    <measurement group_id="B3" value="69.7" spread="8.4"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With PSA Response</title>
        <description>PSA response was defined as ≥50% decrease in PSA levels in both treatment arms from baseline, during the whole treatment, before treatment switch and after treatment switch. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart). Because the purpose of this study is to explore the benefit of a regimen in which participants are switched to a different taxane if PSA does not decrease ≥30% after 4 cycles, irrespective of which agent (docetaxel or cabazitaxel) is administered initially, the data for participants who began treatment with docetaxel and for those who began treatment with cabazitaxel were combined for the efficacy analyses.</description>
        <time_frame>Baseline, Pre-dose every 3 weeks, 30 days after last treatment administration (End of treatment [EOT]), every 3 months (for 1 year) then every 6 months until PSA progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With PSA Response</title>
          <description>PSA response was defined as ≥50% decrease in PSA levels in both treatment arms from baseline, during the whole treatment, before treatment switch and after treatment switch. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart). Because the purpose of this study is to explore the benefit of a regimen in which participants are switched to a different taxane if PSA does not decrease ≥30% after 4 cycles, irrespective of which agent (docetaxel or cabazitaxel) is administered initially, the data for participants who began treatment with docetaxel and for those who began treatment with cabazitaxel were combined for the efficacy analyses.</description>
          <population>Analysis was performed on all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>PSA response before switch</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="39.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PSA response after switch</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Overall PSA response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Drug-target Engagement in Circulating Tumor Cells (CTCs): Change From Baseline at Cycle 1 Day 8 in Percent Androgen Receptor Nuclear Localization (%ARNL) by Categories of PSA Decrease From Baseline (≥50%, Not ≥50%) After Cycle 4</title>
        <description>Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained androgen receptor (AR) nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced microtubule bundling (MTB). Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. %ARNL was assessed by quantitative analysis of images of CTCs captured by geometrically enhanced differential immunocapture (GEDI). Reduction from baseline in %ARNL (percentage of total cellular AR that is located in the nucleus) may indicate inhibition of AR signaling. Change from baseline in %ARNL at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥50%, Not ≥50%) after Cycle 4.</description>
        <time_frame>Baseline and Cycle 1 Day 8, Cycle 4</time_frame>
        <population>Participants with evaluable CTCs at both baseline and Cycle 1 Day 8, and evaluable PSA result at both baseline and Cycle 4</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Drug-target Engagement in Circulating Tumor Cells (CTCs): Change From Baseline at Cycle 1 Day 8 in Percent Androgen Receptor Nuclear Localization (%ARNL) by Categories of PSA Decrease From Baseline (≥50%, Not ≥50%) After Cycle 4</title>
          <description>Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained androgen receptor (AR) nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced microtubule bundling (MTB). Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. %ARNL was assessed by quantitative analysis of images of CTCs captured by geometrically enhanced differential immunocapture (GEDI). Reduction from baseline in %ARNL (percentage of total cellular AR that is located in the nucleus) may indicate inhibition of AR signaling. Change from baseline in %ARNL at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥50%, Not ≥50%) after Cycle 4.</description>
          <population>Participants with evaluable CTCs at both baseline and Cycle 1 Day 8, and evaluable PSA result at both baseline and Cycle 4</population>
          <units>percentage ARNL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>PSA decreased ≥50% at Cycle 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-17.58" spread="21.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PSA not decreased ≥50% at Cycle 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.30" spread="11.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>%ARNL change from baseline at Cycle 1 Day 8 in participants with ≥50% decrease in PSA at Cycle 4 was compared with that of participants who did not have ≥50% decrease in PSA at Cycle 4</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>PFS was defined as the time interval between the date of random allocation of the treatment and the date of first documentation of any of the following: radiographic tumor progression (using Modified Response Evaluation Criteria in Solid Tumors [RECIST1.1] before any switch and during the study), clinical progression (including skeletal-related events, increasing pain requiring escalation of narcotic analgesics, urinary obstruction), PSA progression or death from any cause. Analysis was performed by Kaplan Meier method.</description>
        <time_frame>From Baseline until DP or death due to any cause or study cut off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>PFS was defined as the time interval between the date of random allocation of the treatment and the date of first documentation of any of the following: radiographic tumor progression (using Modified Response Evaluation Criteria in Solid Tumors [RECIST1.1] before any switch and during the study), clinical progression (including skeletal-related events, increasing pain requiring escalation of narcotic analgesics, urinary obstruction), PSA progression or death from any cause. Analysis was performed by Kaplan Meier method.</description>
          <population>Analysis was performed on all randomized participants.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Before switch</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.1" lower_limit="3.81" upper_limit="NA">The upper bound of the confidence interval could not be estimated because of insufficient number of events for before switch PFS.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Whole treatment continuum</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.1" lower_limit="4.93" upper_limit="11.70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PSA Progression Free Survival</title>
        <description>PSA progression-free survival before any switch and PSA progression free survival during the study was defined as the time interval between the date of Day 1 of Cycle 1 to the date of either first PSA progression or death due to any cause whichever came first. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart).</description>
        <time_frame>From Baseline until DP or death due to any cause or study cut off date, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on all randomized population.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>PSA Progression Free Survival</title>
          <description>PSA progression-free survival before any switch and PSA progression free survival during the study was defined as the time interval between the date of Day 1 of Cycle 1 to the date of either first PSA progression or death due to any cause whichever came first. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart).</description>
          <population>Analysis was performed on all randomized population.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Before switch</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="3.09" upper_limit="NA">The median and upper bound of the confidence interval could not be estimated because of insufficient number of events for before switch PSA PFS.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>whole treatment continuum</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.4" lower_limit="8.31" upper_limit="NA">The upper bound of the confidence interval could not be estimated because of insufficient number of events for whole treatment continuum PSA PFS.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Objective Response</title>
        <time_frame>From baseline until DP or study cut off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>No data was collected to determine the Objective Response, hence this outcome measure was not evaluated.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Objective Response</title>
          <population>No data was collected to determine the Objective Response, hence this outcome measure was not evaluated.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Radiographic Progression-free Survival (rPFS)</title>
        <time_frame>From baseline, every 12 weeks until radiological tumor progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Radiographic Progression-free Survival (rPFS)</title>
          <population>Analysis was performed on all randomized participants.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Kaplan-Meier was not analyzed, as less than 50% population had the event. Hence, data was not calculated and reported.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Progression-free Survival (cPFS)</title>
        <description>cPFS was assessed before switch and during the study including skeletal-related events (SRE), increasing pain requiring escalation of narcotic analgesics, urinary obstruction, etc. SRE included pathological fractures and/or spinal cord compression, need for bone irradiation (including radioisotopes or bone surgery), change of antineoplastic therapy (including introduction of bisphosphonates or denosumab in the face of increase in pain) to treat bone pain. Pain was assessed using present pain intensity (PPI) scale (0=no pain, up to 5=excruciating pain) and analgesics used for cancer pain (1 point for non-narcotic medications and 4 points for narcotic medications).</description>
        <time_frame>Baseline, Pre-dose every 3 weeks, EOT, every 3 months (for 1 year) until first SRE occurrence or death or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Progression-free Survival (cPFS)</title>
          <description>cPFS was assessed before switch and during the study including skeletal-related events (SRE), increasing pain requiring escalation of narcotic analgesics, urinary obstruction, etc. SRE included pathological fractures and/or spinal cord compression, need for bone irradiation (including radioisotopes or bone surgery), change of antineoplastic therapy (including introduction of bisphosphonates or denosumab in the face of increase in pain) to treat bone pain. Pain was assessed using present pain intensity (PPI) scale (0=no pain, up to 5=excruciating pain) and analgesics used for cancer pain (1 point for non-narcotic medications and 4 points for narcotic medications).</description>
          <population>Analysis was performed on all randomized participants.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Before switch</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="7.16" upper_limit="NA">The median and upper bound of the confidence interval could not be estimated because of insufficient number of events for before switch cPFS.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Whole treatment continuum</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Kaplan-Meier was not analyzed, as less than 50% population had the event. Hence, data was not calculated and reported.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall survival before switch and overall survival during the study was defined as the time interval from the date of random allocation to the date of death due to any cause until study cut-off date.</description>
        <time_frame>From baseline until death due to any cause or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall survival before switch and overall survival during the study was defined as the time interval from the date of random allocation to the date of death due to any cause until study cut-off date.</description>
          <population>Analysis was performed on all randomized participants.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Before switch</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.8" lower_limit="4.01" upper_limit="NA">Not enough events were reported to calculate Kaplan-Meier curve.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>whole treatment continuum</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="14.03" upper_limit="NA">Not enough events were reported to calculate Kaplan-Meier curve.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With ≥30% and ≥50% Reduction in PSA Response</title>
        <description>Participants with ≥30% and ≥50% reduction in PSA response from base line were evaluated in participants who were previously treated with a high potency androgen receptor (AR)-targeted agent (AR signaling inhibitor or cytochrome P450 17 alphahydroxylase/17,20lyase [CYP 17] inhibitor).</description>
        <time_frame>From baseline until DP or study cut-off, whichever was earlier (Maximum duration: 60 weeks)</time_frame>
        <population>Analysis was performed on as-treated population that included all participants who received initial taxane treatment and had a post treatment assessment. Number of participants analyzed=participants treated/non-treated with AR-target agent and with PSA response assessment at specified time-points.</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (AR-target Agent Treated)</title>
            <description>Participants having prior treatment experience with a high potency AR targeted agent (AR signaling inhibitor or CYP 17) before this study.</description>
          </group>
          <group group_id="O2">
            <title>Overall Population (Non AR-target Agent Treated)</title>
            <description>Participants not having prior treatment experience with a high potency AR targeted agent (AR signaling inhibitor or CYP 17 inhibitor) before this study.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With ≥30% and ≥50% Reduction in PSA Response</title>
          <description>Participants with ≥30% and ≥50% reduction in PSA response from base line were evaluated in participants who were previously treated with a high potency androgen receptor (AR)-targeted agent (AR signaling inhibitor or cytochrome P450 17 alphahydroxylase/17,20lyase [CYP 17] inhibitor).</description>
          <population>Analysis was performed on as-treated population that included all participants who received initial taxane treatment and had a post treatment assessment. Number of participants analyzed=participants treated/non-treated with AR-target agent and with PSA response assessment at specified time-points.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
                <count group_id="O2" value="35"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>≥30% reduction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.0"/>
                    <measurement group_id="O2" value="74.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥50% reduction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.0"/>
                    <measurement group_id="O2" value="68.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Drug-target Engagement in CTCs: Change From Baseline at Cycle 1 Day 8 in MTB by Categories of PSA Decrease From Baseline (≥30%, Not ≥30%) After Cycle 4</title>
        <description>Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained AR nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced MTB. Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. MTB in images of CTCs captured by GEDI was qualitatively assessed by three independent operators for increase compared with baseline on a scale of 0 to 3 from no to most MTB increase. Increase from baseline in MTB may indicate inhibition of AR signaling. Change from baseline in MTB at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥30%, Not ≥30%) after Cycle 4.</description>
        <time_frame>Baseline and Cycle 1 Day 8, Cycle 4</time_frame>
        <population>Participants with evaluable CTCs at both baseline and Cycle 1 Day 8, and evaluable PSA result at both baseline and Cycle 4</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Population (Treatment A or Treatment B)</title>
            <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4, switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Drug-target Engagement in CTCs: Change From Baseline at Cycle 1 Day 8 in MTB by Categories of PSA Decrease From Baseline (≥30%, Not ≥30%) After Cycle 4</title>
          <description>Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained AR nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced MTB. Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. MTB in images of CTCs captured by GEDI was qualitatively assessed by three independent operators for increase compared with baseline on a scale of 0 to 3 from no to most MTB increase. Increase from baseline in MTB may indicate inhibition of AR signaling. Change from baseline in MTB at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥30%, Not ≥30%) after Cycle 4.</description>
          <population>Participants with evaluable CTCs at both baseline and Cycle 1 Day 8, and evaluable PSA result at both baseline and Cycle 4</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>PSA decreased ≥30% at Cycle 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.69" spread="0.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PSA not decreased ≥30% at Cycle 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.09" spread="0.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>MTB change from baseline at Cycle 1 Day 8 in participants with ≥30% decrease in PSA at Cycle 4 was compared with that of participants who did not have ≥30% decrease in PSA at Cycle 4</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0927</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <desc>Reported AEs are treatment emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (from the time of first dose until 30 days after the last treatment administration). Safety population includes all treated participants.</desc>
      <group_list>
        <group group_id="E1">
          <title>Docetaxel + Prednisone (Treatment A) - Throughout</title>
          <description>Docetaxel 75 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment throughout until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
        </group>
        <group group_id="E2">
          <title>Cabazitaxel + Prednisone (Treatment B) - Throughout</title>
          <description>Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment throughout until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
        </group>
        <group group_id="E3">
          <title>Switched Population (Treatment A to B or Treatment B to A)</title>
          <description>Docetaxel 75 mg/m^2 or Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with &lt;30% PSA reduction from baseline at the end of Cycle 4 switched to Cabazitaxel 25 mg/m^2 IV or Docetaxel 75mg/m^2 IV infusion respectively on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 18.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Supraventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pneumoperitoneum</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Localised oedema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaphylactoid reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Septic shock</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Hip fracture</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Spinal compression fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Nerve compression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nerve root compression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </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" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 18.0</default_vocab>
        <default_assessment>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="26" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Arrhythmia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Hearing impaired</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Lacrimation increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vitreous haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Visual acuity reduced</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vitreous floaters</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Haemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Proctalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Faeces soft</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Abdominal pain lower</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Haematochezia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Melaena</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Rectal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Salivary hypersecretion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Tongue discolouration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hyperthermia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Adverse drug reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Exercise tolerance decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Facial pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Infusion site extravasation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Peripheral swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Temperature intolerance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatomegaly</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Bronchopneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Catheter site cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Enterobacter infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Fungal skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gastroenteritis viral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Oral fungal infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Septic phlebitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Skin abrasion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Spinal compression fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Musculoskeletal stiffness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Oncologic complication</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Aphonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Burning sensation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nerve compression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pollakiuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Bladder spasm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Cystitis noninfective</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hydronephrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hypertonic bladder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Penile pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Scrotal oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Upper-airway cough syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dyspnoea exertional</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Increased upper airway secretion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nasal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Respiratory distress</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nail ridging</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nail discolouration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Actinic keratosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nail disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nail hypertrophy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Night sweats</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Petechiae</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Skin tightness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hot flush</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pallor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
              </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>If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Trial Transparency Team</name_or_title>
      <organization>Sanofi</organization>
      <email>Contact-US@sanofi.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/NCT01718353
org study id: CABAZL06056
secondary id: U1111-1130-9893
nct id: NCT01718353
lead sponsor: 
has dmc: No
Docetaxel and cabazitaxel are cancer chemotherapy agents of the taxane drug class. The
      purpose of this study is to explore the benefit, for treatment of metastatic
      castration-resistant prostate cancer (mCRPC), of a regimen in which participants begin
      treatment with either of these two taxane drugs (docetaxel or cabazitaxel, in combination
      with prednisone) and are switched to the other taxane drug if prostate-specific antigen (PSA)
      value does not decrease ≥30% after 4 cycles. As defined in study protocol amendment 3,
      efficacy results are summarized for all participants combined, irrespective of which agent
      (docetaxel or cabazitaxel) was administered initially, rather than separately for the two
      groups based on taxane administered initially. One of the primary outcome measures is
      percentage of participants with a ≥50% sustained decrease from baseline in PSA at any time
      during the trial. By providing an opportunity for patients to switch taxane based on early
      PSA response, there may be a difference in result for this measure versus result in a study
      where it was not possible to switch. The other primary outcome measures are change from
      baseline in circulating tumor cells (CTCs) biomarkers percent androgen receptor nuclear
      localization (%ARNL) and microtubule bundling (MTB).
-  Participants were treated until progressive disease, unacceptable toxicity, death, or
           participant's refusal of further study treatment. All participants were followed until
           death or the study cut-off date, whichever came first.

        -  Study cut-off was 1 month after the last participant last treatment.

        -  Participants alive at the cut-off date were not followed for overall survival.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Participants With PSA Response
time frame: Baseline, Pre-dose every 3 weeks, 30 days after last treatment administration (End of treatment [EOT]), every 3 months (for 1 year) then every 6 months until PSA progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
description: PSA response was defined as ≥50% decrease in PSA levels in both treatment arms from baseline, during the whole treatment, before treatment switch and after treatment switch. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/ml] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart). Because the purpose of this study is to explore the benefit of a regimen in which participants are switched to a different taxane if PSA does not decrease ≥30% after 4 cycles, irrespective of which agent (docetaxel or cabazitaxel) is administered initially, the data for participants who began treatment with docetaxel and for those who began treatment with cabazitaxel were combined for the efficacy analyses.
measure: Drug-target Engagement in Circulating Tumor Cells (CTCs): Change From Baseline at Cycle 1 Day 8 in Percent Androgen Receptor Nuclear Localization (%ARNL) by Categories of PSA Decrease From Baseline (≥50%, Not ≥50%) After Cycle 4
time frame: Baseline and Cycle 1 Day 8, Cycle 4
description: Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained androgen receptor (AR) nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced microtubule bundling (MTB). Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. %ARNL was assessed by quantitative analysis of images of CTCs captured by geometrically enhanced differential immunocapture (GEDI). Reduction from baseline in %ARNL (percentage of total cellular AR that is located in the nucleus) may indicate inhibition of AR signaling. Change from baseline in %ARNL at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥50%, Not ≥50%) after Cycle 4.
measure: Drug-target Engagement in CTCs: Change From Baseline at Cycle 1 Day 8 in MTB by Categories of PSA Decrease From Baseline (≥30%, Not ≥30%) After Cycle 4
time frame: Baseline and Cycle 1 Day 8, Cycle 4
description: Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained AR nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced MTB. Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. MTB in images of CTCs captured by GEDI was qualitatively assessed by three independent operators for increase compared with baseline on a scale of 0 to 3 from no to most MTB increase. Increase from baseline in MTB may indicate inhibition of AR signaling. Change from baseline in MTB at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥30%, Not ≥30%) after Cycle 4.
measure: Progression Free Survival (PFS)
time frame: From Baseline until DP or death due to any cause or study cut off, whichever was earlier (Maximum duration: 60 weeks)
description: PFS was defined as the time interval between the date of random allocation of the treatment and the date of first documentation of any of the following: radiographic tumor progression (using Modified Response Evaluation Criteria in Solid Tumors [RECIST1.1] before any switch and during the study), clinical progression (including skeletal-related events, increasing pain requiring escalation of narcotic analgesics, urinary obstruction), PSA progression or death from any cause. Analysis was performed by Kaplan Meier method.
measure: PSA Progression Free Survival
time frame: From Baseline until DP or death due to any cause or study cut off date, whichever was earlier (Maximum duration: 60 weeks)
description: PSA progression-free survival before any switch and PSA progression free survival during the study was defined as the time interval between the date of Day 1 of Cycle 1 to the date of either first PSA progression or death due to any cause whichever came first. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% [at least 2ng/mL] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart).
measure: Percentage of Participants With Objective Response
time frame: From baseline until DP or study cut off, whichever was earlier (Maximum duration: 60 weeks)
measure: Radiographic Progression-free Survival (rPFS)
time frame: From baseline, every 12 weeks until radiological tumor progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
measure: Clinical Progression-free Survival (cPFS)
time frame: Baseline, Pre-dose every 3 weeks, EOT, every 3 months (for 1 year) until first SRE occurrence or death or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
description: cPFS was assessed before switch and during the study including skeletal-related events (SRE), increasing pain requiring escalation of narcotic analgesics, urinary obstruction, etc. SRE included pathological fractures and/or spinal cord compression, need for bone irradiation (including radioisotopes or bone surgery), change of antineoplastic therapy (including introduction of bisphosphonates or denosumab in the face of increase in pain) to treat bone pain. Pain was assessed using present pain intensity (PPI) scale (0=no pain, up to 5=excruciating pain) and analgesics used for cancer pain (1 point for non-narcotic medications and 4 points for narcotic medications).
measure: Overall Survival
time frame: From baseline until death due to any cause or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
description: Overall survival before switch and overall survival during the study was defined as the time interval from the date of random allocation to the date of death due to any cause until study cut-off date.
measure: Percentage of Participants With ≥30% and ≥50% Reduction in PSA Response
time frame: From baseline until DP or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
description: Participants with ≥30% and ≥50% reduction in PSA response from base line were evaluated in participants who were previously treated with a high potency androgen receptor (AR)-targeted agent (AR signaling inhibitor or cytochrome P450 17 alphahydroxylase/17,20lyase [CYP 17] inhibitor).
arm group label: Docetaxel + Prednisone (Treatment A)
arm group type: Experimental
description: Docetaxel 75 mg/m^2 intravenous (IV) infusion on Day 1 of Cycle 1 and every 3 weeks (q3w) thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with <30% PSA reduction from baseline at the end of Cycle 4 switched to Cabazitaxel 25mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until disease progression (DP), death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.
arm group label: Cabazitaxel + Prednisone (Treatment B)
arm group type: Experimental
description: Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with <30% PSA reduction from baseline at the end of Cycle 4 switched to Docetaxel 75mg/m^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.
intervention type: Drug
intervention name: DOCETAXEL (XRP6976)
description: Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous
arm group label: Docetaxel + Prednisone (Treatment A)
other name: Taxotere®
intervention type: Drug
intervention name: CABAZITAXEL (XRP6258)
description: Pharmaceutical form: Concentrate and solvent for solution for infusion Route of administration: Intravenous
arm group label: Cabazitaxel + Prednisone (Treatment B)
other name: Jevtana®
intervention type: Drug
intervention name: Prednisone
description: Pharmaceutical form: Tablet Route of administration: Oral
arm group label: Cabazitaxel + Prednisone (Treatment B)
arm group label: Docetaxel + Prednisone (Treatment A)
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
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country: Canada
country: United States
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Prednisone
mesh term: Docetaxel
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 