<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/NCT01722487</url>
  </required_header>
  <id_info>
    <org_study_id>PCYC-1115-CA</org_study_id>
    <secondary_id>2012-003967-23</secondary_id>
    <nct_id>NCT01722487</nct_id>
  </id_info>
  <brief_title>Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL</brief_title>
  <official_title>Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pharmacyclics LLC.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Janssen Research &amp; Development, LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Pharmacyclics LLC.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase&#xD;
      Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive&#xD;
      Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to&#xD;
      compare the safety and efficacy of Ibrutinib versus Chlorambucil in treatment-naive patients&#xD;
      65 years or older who have CLL or SLL.&#xD;
&#xD;
      Eligible patients will be randomized in a 1:1 ratio to Treatment Arm A or B:&#xD;
&#xD;
        -  Treatment Arm A: Oral Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle; the&#xD;
           dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of each&#xD;
           cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of 12&#xD;
           cycles, in the absence of progressive disease or unacceptable toxicity.&#xD;
&#xD;
        -  Treatment Arm B: Oral Ibrutinib 420 mg/day Randomization will be stratified on Eastern&#xD;
           Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of&#xD;
           advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic&#xD;
           region: US versus non-US.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2013</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PFS (Progression Free Survival)</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS&#xD;
Progressive disease according to 2008 IWCLL guidelines was defined as:&#xD;
Group A&#xD;
Lymphadenopathy, increase ≥50%&#xD;
Hepatomegaly, increase ≥50%&#xD;
Splenomegaly, increase ≥50%&#xD;
Blood lymphocytes, increase ≥ 50% over baseline&#xD;
Group B&#xD;
Platelets counts, decrease of ≥ 50% from baseline secondary to CLL&#xD;
Hemoglobin, decrease of &gt; 2 g/dL from baseline secondary to CLL</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ORR (Overall Response Rate)</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Sustained Hemoglobin Improvement</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>The proportion of subjects who achieved Hemoglobin &gt;11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin &gt;11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Sustained Platelet Improvement</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>The proportion of subjects who achieved platelet &gt;100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia</measure>
    <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
    <description>In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet &gt;100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">269</enrollment>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <condition>Small Lymphocytic Lymphoma</condition>
  <arm_group>
    <arm_group_label>Ibrutinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chlorambucil</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle.The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.</description>
    <arm_group_label>Ibrutinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chlorambucil</intervention_name>
    <description>Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.</description>
    <arm_group_label>Chlorambucil</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males or females of 65 years of age or greater. Patients between the ages of 65 and 70&#xD;
             years of age must have 1 or more of the following comorbidities that may preclude the&#xD;
             use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or rituximab:&#xD;
&#xD;
               -  creatinine clearance &lt; 70 mL/min using the Cockcroft-Gault equation&#xD;
&#xD;
               -  platelet count &lt; 100,000/μL or hemoglobin &lt; 10 g/dL&#xD;
&#xD;
               -  clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune&#xD;
                  thrombocytopenia)&#xD;
&#xD;
               -  ECOG performance score = 1 or 2&#xD;
&#xD;
          2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)&#xD;
&#xD;
          3. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for&#xD;
             requiring treatment:&#xD;
&#xD;
               -  Evidence of progressive marrow failure as manifested by the development of, or&#xD;
                  worsening of, anemia and/or thrombocytopenia Massive, progressive, or symptomatic&#xD;
                  splenomegaly&#xD;
&#xD;
               -  Massive nodes or progressive or symptomatic lymphadenopathy&#xD;
&#xD;
               -  Progressive lymphocytosis&#xD;
&#xD;
               -  Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly&#xD;
                  responsive to corticosteroids or standard therapy&#xD;
&#xD;
               -  Constitutional symptoms&#xD;
&#xD;
          4. Measurable nodal disease by computed tomography (CT)&#xD;
&#xD;
          5. ECOG performance status of 0-2&#xD;
&#xD;
          6. Life expectancy &gt; 4 months from randomization&#xD;
&#xD;
          7. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL&#xD;
             (independent of growth factor support for at least 7 days prior to screening) and&#xD;
             platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for&#xD;
             at least 7 days prior to screening)&#xD;
&#xD;
          8. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine&#xD;
             transaminase (ALT) &lt; 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x&#xD;
             ULN&#xD;
&#xD;
          9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using&#xD;
             the Cockcroft-Gault equation&#xD;
&#xD;
         10. Willingness to receive all outpatient treatment, all laboratory monitoring, and all&#xD;
             radiological evaluations at the institution that administers study drug for the entire&#xD;
             study&#xD;
&#xD;
         11. Willingness of male patients, if sexually active with a female of childbearing&#xD;
             potential, to use an effective barrier method of contraception during the study and&#xD;
             for 3 months following the last dose of study drug&#xD;
&#xD;
         12. Ability to provide written informed consent and to understand and comply with the&#xD;
             requirements of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known involvement of the central nervous system by lymphoma or leukemia&#xD;
&#xD;
          2. History or current evidence of Richter's transformation or prolymphocytic leukemia&#xD;
&#xD;
          3. Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more than&#xD;
             20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) or&#xD;
             cytogenetic evaluation&#xD;
&#xD;
          4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura&#xD;
&#xD;
          5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies)&#xD;
             intended specifically to treat CLL/SLL&#xD;
&#xD;
          6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to&#xD;
             randomization&#xD;
&#xD;
          7. Corticosteroid use within 1 week prior to first dose of study drug, with the exception&#xD;
             of inhaled, topical, or other local administrations. Patients requiring systemic&#xD;
             steroids at daily doses &gt; 20 mg prednisone (or corticosteroid equivalent, see Appendix&#xD;
             N), or those who are administered steroids for leukemia control or white blood cell&#xD;
             (WBC)-count-lowering are excluded.&#xD;
&#xD;
          8. Major surgery within 4 weeks prior to randomization&#xD;
&#xD;
          9. History of prior malignancy, with the exception of the following:&#xD;
&#xD;
               -  malignancy treated with curative intent and with no evidence of active disease&#xD;
                  present for more than 3 years prior to screening and felt to be at low risk for&#xD;
                  recurrence by treating physician&#xD;
&#xD;
               -  adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma&#xD;
                  without current evidence of disease&#xD;
&#xD;
               -  adequately treated cervical carcinoma in situ without current evidence of disease&#xD;
&#xD;
         10. Currently active, clinically significant cardiovascular disease or a history of&#xD;
             myocardial infarction within 6 months prior to randomization&#xD;
&#xD;
         11. Inability to swallow capsules or tablets, or disease significantly affecting&#xD;
             gastrointestinal function&#xD;
&#xD;
         12. Uncontrolled active systemic fungal, bacterial, viral, or other infection or&#xD;
             requirement for intravenous (IV) antibiotics&#xD;
&#xD;
         13. Known history of infection with human immunodeficiency virus (HIV)&#xD;
&#xD;
         14. Serologic status reflecting active hepatitis B or C infection&#xD;
&#xD;
         15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment&#xD;
&#xD;
         16. Current life-threatening illness, medical condition, or organ-system dysfunction that&#xD;
             could compromise patient safety or put the study at risk&#xD;
&#xD;
         17. Requirement for anticoagulation with warfarin&#xD;
&#xD;
         18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lori Styles, MD</last_name>
    <role>Study Director</role>
    <affiliation>Pharmacyclics LLC.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #047</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #408</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #720</name>
      <address>
        <city>Santa Rosa</city>
        <state>California</state>
        <zip>95403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #038</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #125</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30318</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #126</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #071</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #307</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #387</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #221</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #712</name>
      <address>
        <city>Las Vegas</city>
        <state>Nevada</state>
        <zip>89169</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #350</name>
      <address>
        <city>New Hyde Park</city>
        <state>New York</state>
        <zip>11042</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #127</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #656</name>
      <address>
        <city>Goldsboro</city>
        <state>North Carolina</state>
        <zip>27534</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #734</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #677</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97227</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #050</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #032</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #381</name>
      <address>
        <city>Laredo</city>
        <state>Texas</state>
        <zip>78041</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #653</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #404</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #731</name>
      <address>
        <city>Walla Walla</city>
        <state>Washington</state>
        <zip>99362</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #654</name>
      <address>
        <city>Kogarah</city>
        <state>New South Wales</state>
        <zip>2217</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #503</name>
      <address>
        <city>Woolloongabba</city>
        <state>Queensland</state>
        <zip>4102</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #163</name>
      <address>
        <city>Bedford Park</city>
        <state>South Australia</state>
        <zip>5042</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #555</name>
      <address>
        <city>Hobart</city>
        <state>Tasmania</state>
        <zip>7000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #193</name>
      <address>
        <city>Box Hill</city>
        <state>Victoria</state>
        <zip>3128</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #556</name>
      <address>
        <city>Clayton</city>
        <state>Victoria</state>
        <zip>3168</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #501</name>
      <address>
        <city>Fitzroy</city>
        <state>Victoria</state>
        <zip>3065</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #715</name>
      <address>
        <city>Frankston</city>
        <state>Victoria</state>
        <zip>3199</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #558</name>
      <address>
        <city>Geelong</city>
        <state>Victoria</state>
        <zip>3220</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #170</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #164</name>
      <address>
        <city>Bruxelles</city>
        <state>Brussells</state>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #727</name>
      <address>
        <city>Yvoir</city>
        <state>Namur</state>
        <zip>5530</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #560</name>
      <address>
        <city>Gent</city>
        <state>Oost-Vlaanderen</state>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #559</name>
      <address>
        <city>Leuven</city>
        <state>Vlaams Brabant</state>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #628</name>
      <address>
        <city>Brugge</city>
        <state>West-Vlaanderen</state>
        <zip>8000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #561</name>
      <address>
        <city>Antwerpen</city>
        <zip>2060</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #184</name>
      <address>
        <city>Brussells</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #157</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T2N 4N2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #018</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #159</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #674</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #671</name>
      <address>
        <city>Nanjing</city>
        <state>Jiangsu</state>
        <zip>210029</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #675</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>31003</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #670</name>
      <address>
        <city>Beijing</city>
        <zip>100142</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #673</name>
      <address>
        <city>Beijing</city>
        <zip>100191</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #564</name>
      <address>
        <city>Hradec Kralove</city>
        <state>Kralovehradecky Kraj</state>
        <zip>500 05</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #562</name>
      <address>
        <city>Brno</city>
        <zip>625 00</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #566</name>
      <address>
        <city>Plzen-Lochotin</city>
        <zip>304 60</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #572</name>
      <address>
        <city>Dublin</city>
        <zip>7</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #570</name>
      <address>
        <city>Dublin</city>
        <zip>8</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #571</name>
      <address>
        <city>Galway</city>
        <zip>ST4 6QG</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #573</name>
      <address>
        <city>Haifa</city>
        <zip>31048</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #576</name>
      <address>
        <city>Haifa</city>
        <zip>31096</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #577</name>
      <address>
        <city>Jerusalem</city>
        <zip>91031</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #578</name>
      <address>
        <city>Nahariya</city>
        <zip>22100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #575</name>
      <address>
        <city>Petaẖ Tiqwa</city>
        <zip>49100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #574</name>
      <address>
        <city>Ramat Gan</city>
        <zip>52621</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #583</name>
      <address>
        <city>Roma</city>
        <state>Lazio</state>
        <zip>00161</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #522</name>
      <address>
        <city>Rozzano</city>
        <state>Milano</state>
        <zip>20089</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #582</name>
      <address>
        <city>Novara</city>
        <state>Piemonte</state>
        <zip>28100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #527</name>
      <address>
        <city>Padova</city>
        <state>Veneto</state>
        <zip>35128</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #580</name>
      <address>
        <city>Bologna</city>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #584</name>
      <address>
        <city>Milano</city>
        <zip>20122</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #523</name>
      <address>
        <city>Milano</city>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #581</name>
      <address>
        <city>Milano</city>
        <zip>20162</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #524</name>
      <address>
        <city>Modena</city>
        <zip>41100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #589</name>
      <address>
        <city>Christchurch</city>
        <state>Canterbury</state>
        <zip>8011</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #586</name>
      <address>
        <city>Hamilton</city>
        <state>Waikato</state>
        <zip>3240</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #663</name>
      <address>
        <city>Auckland</city>
        <zip>0622</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #588</name>
      <address>
        <city>Auckland</city>
        <zip>1023</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #587</name>
      <address>
        <city>Wellington</city>
        <zip>6021</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #590</name>
      <address>
        <city>Lublin</city>
        <state>Lubelskie</state>
        <zip>20-081</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #592</name>
      <address>
        <city>Brzozowie</city>
        <state>Podkarpackie</state>
        <zip>36.200</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #591</name>
      <address>
        <city>Chorzow</city>
        <zip>40</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #529</name>
      <address>
        <city>Gdansk</city>
        <zip>80-952</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #531</name>
      <address>
        <city>Lodz</city>
        <zip>93-510</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #707</name>
      <address>
        <city>Ryazan</city>
        <zip>390039</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #304</name>
      <address>
        <city>Yaroslavl</city>
        <zip>150062</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #536</name>
      <address>
        <city>Majadahonda</city>
        <state>Madrid</state>
        <zip>28222</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #534</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #533</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #535</name>
      <address>
        <city>Barcelona</city>
        <zip>08041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #604</name>
      <address>
        <city>Barcelona</city>
        <zip>08908</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #537</name>
      <address>
        <city>Madrid</city>
        <zip>28050</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #608</name>
      <address>
        <city>Ankara</city>
        <zip>06500</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #606</name>
      <address>
        <city>Ankara</city>
        <zip>06590</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #599</name>
      <address>
        <city>Istanbul</city>
        <zip>34390</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #714</name>
      <address>
        <city>Izmir</city>
        <zip>35040</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #601</name>
      <address>
        <city>Izmir</city>
        <zip>35340</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #602</name>
      <address>
        <city>Kayseri</city>
        <zip>38039</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #597</name>
      <address>
        <city>Cherkasy</city>
        <state>Cherkas'ka Oblast</state>
        <zip>18009</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #594</name>
      <address>
        <city>Dnipropetrovsk</city>
        <state>Dnipropetrovs'ka Oblast'</state>
        <zip>49102</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #725</name>
      <address>
        <city>Kharkiv</city>
        <state>Kharkivs'ka Oblast</state>
        <zip>61070</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #596</name>
      <address>
        <city>Lviv</city>
        <state>L'vivs'ka Oblast</state>
        <zip>79044</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #598</name>
      <address>
        <city>Simferopol</city>
        <state>Respublika Krym</state>
        <zip>95023</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #595</name>
      <address>
        <city>Vinnytsia</city>
        <state>Vinnyts'ka Oblast</state>
        <zip>21018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #724</name>
      <address>
        <city>Zhytomyr</city>
        <state>Zhytomyrs'ka Oblast'</state>
        <zip>10022</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #551</name>
      <address>
        <city>Bournemouth</city>
        <state>Dorset</state>
        <zip>BH7 7DW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #544</name>
      <address>
        <city>London</city>
        <state>England</state>
        <zip>SE5 9RS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #668</name>
      <address>
        <city>Oxford</city>
        <state>England</state>
        <zip>OX3 7LE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #549</name>
      <address>
        <city>Colchester</city>
        <state>Essex</state>
        <zip>CO4 5JL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #607</name>
      <address>
        <city>Cardiff</city>
        <state>South Glamergon</state>
        <zip>CF14 4XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #550</name>
      <address>
        <city>Leeds</city>
        <state>Yorkshire</state>
        <zip>LS9 7TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #721</name>
      <address>
        <city>Birmingham</city>
        <zip>B9 5SS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #548</name>
      <address>
        <city>Nottingham</city>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Reference ID/Investigator #367</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Belgium</country>
    <country>Canada</country>
    <country>China</country>
    <country>Czechia</country>
    <country>Ireland</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>New Zealand</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Turkey</country>
    <country>Ukraine</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
  </removed_countries>
  <link>
    <url>http://www.pharmacyclics.com</url>
    <description>www.pharmacyclics.com</description>
  </link>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>October 29, 2012</study_first_submitted>
  <study_first_submitted_qc>November 2, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 6, 2012</study_first_posted>
  <results_first_submitted>March 31, 2016</results_first_submitted>
  <results_first_submitted_qc>March 31, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">May 4, 2016</results_first_posted>
  <last_update_submitted>November 27, 2017</last_update_submitted>
  <last_update_submitted_qc>November 27, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 30, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CLL, SLL</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chlorambucil</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>We share this information with FDA and other authorities for the purposes of analyzing the study but not with other researchers</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Ibrutinib</title>
          <description>Ibrutinib 420 mg daily.</description>
        </group>
        <group group_id="P2">
          <title>Chlorambucil</title>
          <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="136"/>
                <participants group_id="P2" count="133"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="134">Participants who were still on study or died at study closure</participants>
                <participants group_id="P2" count="126">Participants who were still on study or died at study closure</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ibrutinib</title>
          <description>Ibrutinib 420 mg daily.</description>
        </group>
        <group group_id="B2">
          <title>Chlorambucil</title>
          <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</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="136"/>
            <count group_id="B2" value="133"/>
            <count group_id="B3" value="269"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</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>Between 18 and 65 years</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>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="136"/>
                    <measurement group_id="B2" value="133"/>
                    <measurement group_id="B3" value="269"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="73.1" spread="5.67"/>
                    <measurement group_id="B2" value="73.4" spread="5.95"/>
                    <measurement group_id="B3" value="73.3" spread="5.81"/>
                  </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="48"/>
                    <measurement group_id="B2" value="52"/>
                    <measurement group_id="B3" value="100"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="88"/>
                    <measurement group_id="B2" value="81"/>
                    <measurement group_id="B3" value="169"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>PFS (Progression Free Survival)</title>
        <description>The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS&#xD;
Progressive disease according to 2008 IWCLL guidelines was defined as:&#xD;
Group A&#xD;
Lymphadenopathy, increase ≥50%&#xD;
Hepatomegaly, increase ≥50%&#xD;
Splenomegaly, increase ≥50%&#xD;
Blood lymphocytes, increase ≥ 50% over baseline&#xD;
Group B&#xD;
Platelets counts, decrease of ≥ 50% from baseline secondary to CLL&#xD;
Hemoglobin, decrease of &gt; 2 g/dL from baseline secondary to CLL</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Intention to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles.</description>
          </group>
        </group_list>
        <measure>
          <title>PFS (Progression Free Survival)</title>
          <description>The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS&#xD;
Progressive disease according to 2008 IWCLL guidelines was defined as:&#xD;
Group A&#xD;
Lymphadenopathy, increase ≥50%&#xD;
Hepatomegaly, increase ≥50%&#xD;
Splenomegaly, increase ≥50%&#xD;
Blood lymphocytes, increase ≥ 50% over baseline&#xD;
Group B&#xD;
Platelets counts, decrease of ≥ 50% from baseline secondary to CLL&#xD;
Hemoglobin, decrease of &gt; 2 g/dL from baseline secondary to CLL</description>
          <population>Intention to treat</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="136"/>
                <count group_id="O2" value="133"/>
              </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">IBR: Median PFS was not reached so 95% CI for median PFS is not applicable.</measurement>
                    <measurement group_id="O2" value="18.9" lower_limit="14.1" upper_limit="22.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.16</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.09</ci_lower_limit>
            <ci_upper_limit>0.28</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Intention to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.</description>
          <population>Intention to treat</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="136"/>
                <count group_id="O2" value="133"/>
              </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">IBR: Median OS was not reached so 95% CI for median OS is not applicable.</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">CHL: Median OS was not reached so 95% CI for median OS is not applicable.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0010</p_value>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.16</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.05</ci_lower_limit>
            <ci_upper_limit>0.56</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>ORR (Overall Response Rate)</title>
        <description>ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Intention to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
          </group>
        </group_list>
        <measure>
          <title>ORR (Overall Response Rate)</title>
          <description>ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.</description>
          <population>Intention to treat</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="136"/>
                <count group_id="O2" value="133"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="82.4"/>
                    <measurement group_id="O2" value="35.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Sustained Hemoglobin Improvement</title>
        <description>The proportion of subjects who achieved Hemoglobin &gt;11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Intention to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Sustained Hemoglobin Improvement</title>
          <description>The proportion of subjects who achieved Hemoglobin &gt;11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
          <population>Intention to treat</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="136"/>
                <count group_id="O2" value="133"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.6"/>
                    <measurement group_id="O2" value="20.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia</title>
        <description>In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin &gt;11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Subjects with Baseline Anemia</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia</title>
          <description>In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin &gt;11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
          <population>Subjects with Baseline Anemia</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="51"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="84.3"/>
                    <measurement group_id="O2" value="45.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Sustained Platelet Improvement</title>
        <description>The proportion of subjects who achieved platelet &gt;100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Intention to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Sustained Platelet Improvement</title>
          <description>The proportion of subjects who achieved platelet &gt;100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.</description>
          <population>Intention to treat</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="136"/>
                <count group_id="O2" value="133"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.2"/>
                    <measurement group_id="O2" value="11.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>.0009</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia</title>
        <description>In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet &gt;100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.</description>
        <time_frame>Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.</time_frame>
        <population>Subjects With Baseline Thrombocytopenia</population>
        <group_list>
          <group group_id="O1">
            <title>Ibrutinib</title>
            <description>Ibrutinib 420 mg daily.</description>
          </group>
          <group group_id="O2">
            <title>Chlorambucil</title>
            <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia</title>
          <description>In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet &gt;100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.</description>
          <population>Subjects With Baseline Thrombocytopenia</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="35"/>
                <count group_id="O2" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.1"/>
                    <measurement group_id="O2" value="42.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>.0054</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose of study drug to within 30 days of last dose or starting new anti-cancer therapy, whichever occurs earlier, up to 04May2015 ( data cutoff date for final analysis).</time_frame>
      <desc>269 subjects were randomized on the study of which 2 subjects withdrew without treatment and were not included in the number of participants at risk. Investigators assess the occurrence of AEs and SAEs at all patient evaluation time points during the study.</desc>
      <group_list>
        <group group_id="E1">
          <title>PCI-32765</title>
          <description>Ibrutinib 420 mg daily.</description>
        </group>
        <group group_id="E2">
          <title>Chlorambucil</title>
          <description>Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (17.1)</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="55" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Autoimmune haemolytic anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Haemolytic anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lymphadenopathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Aortic valve disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cardiac failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Coronary artery disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Aortic valve disease mixed</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Myocardial ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blindness unilateral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hyphaema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Retinal vascular occlusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Retinal vein occlusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vitreous haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Bile duct stone</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cholangitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hepatitis toxic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Immunodeficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Bronchopneumonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Escherichia sepsis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Abscess limb</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Anal abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Arthritis bacterial</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Clostridium difficile infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Escherichia bacteraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Escherichia infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastroenteritis viral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Klebsiella infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lobar pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lung infection pseudomonal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Neutropenic sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pneumonia bacterial</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pneumonia legionella</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pneumonia viral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Subcutaneous abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Acute hepatitis B</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pneumonia fungal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </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="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Laceration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Limb traumatic amputation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lumbar vertebral fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Muscle strain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Post procedural haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Postoperative wound complication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Radius fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Subdural haematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Toxicity to various agents</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Traumatic haematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Ulna fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Overdose</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Upper limb fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Heart rate irregular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Fibrin D dimer increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </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="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Prostate cancer</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Adenocarcinoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Basosquamous carcinoma of skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Colon adenoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lung adenocarcinoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Non-small cell lung cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma of skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Chronic lymphocytic leukaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cauda equina syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cerebral haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Subarachnoid haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Transient ischaemic attack</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cognitive disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Epilepsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Ischaemic stroke</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Post herpetic neuralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Somatoform disorder cardiovascular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Calculus ureteric</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hydronephrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Renal failure chronic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Renal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Benign prostatic hyperplasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hypercapnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pneumomediastinum</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lung infiltration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Rash macular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Subcutaneous emphysema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Aortic stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Peripheral artery aneurysm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (17.1)</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="133" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="123" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Increased tendency to bruise</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Lacrimation increased</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Visual acuity reduced</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vitreous floaters</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cataract</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="57" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="52" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="50" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="132"/>
              </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="13" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hyperuricaemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="132"/>
              </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="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </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="30" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash erythematous</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Night sweats</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="132"/>
              </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>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Lori Styles, Medical Monitor</name_or_title>
      <organization>Pharmacyclics LLC</organization>
      <phone>+1 (408) 215-3770</phone>
      <email>lstyles@pcyc.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/NCT01722487
org study id: PCYC-1115-CA
secondary id: 2012-003967-23
nct id: NCT01722487
lead sponsor: 
collaborator: 
has dmc: No
A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase
      Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive
      Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.
Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to
      compare the safety and efficacy of Ibrutinib versus Chlorambucil in treatment-naive patients
      65 years or older who have CLL or SLL.

      Eligible patients will be randomized in a 1:1 ratio to Treatment Arm A or B:

        -  Treatment Arm A: Oral Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle; the
           dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of each
           cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of 12
           cycles, in the absence of progressive disease or unacceptable toxicity.

        -  Treatment Arm B: Oral Ibrutinib 420 mg/day Randomization will be stratified on Eastern
           Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of
           advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic
           region: US versus non-US.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: PFS (Progression Free Survival)
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS
Progressive disease according to 2008 IWCLL guidelines was defined as:
Group A
Lymphadenopathy, increase ≥50%
Hepatomegaly, increase ≥50%
Splenomegaly, increase ≥50%
Blood lymphocytes, increase ≥ 50% over baseline
Group B
Platelets counts, decrease of ≥ 50% from baseline secondary to CLL
Hemoglobin, decrease of > 2 g/dL from baseline secondary to CLL
measure: Overall Survival (OS)
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.
measure: ORR (Overall Response Rate)
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.
measure: Proportion of Sustained Hemoglobin Improvement
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: The proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
measure: Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
measure: Proportion of Sustained Platelet Improvement
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: The proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
measure: Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia
time frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.
description: In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.
arm group label: Ibrutinib
arm group type: Experimental
description: Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.
arm group label: Chlorambucil
arm group type: Active Comparator
description: Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle.The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.
intervention type: Drug
intervention name: Ibrutinib
description: Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.
arm group label: Ibrutinib
intervention type: Drug
intervention name: Chlorambucil
description: Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.
arm group label: Chlorambucil
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: No
last name: Lori Styles, MD
role: Study Director
affiliation: Pharmacyclics LLC.
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country: Australia
country: Belgium
country: Canada
country: China
country: Czechia
country: Ireland
country: Israel
country: Italy
country: New Zealand
country: Poland
country: Russian Federation
country: Spain
country: Turkey
country: Ukraine
country: United Kingdom
country: United States
country: Czech Republic
url: http://www.pharmacyclics.com
description: www.pharmacyclics.com
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Chlorambucil
sharing ipd: No
ipd description: We share this information with FDA and other authorities for the purposes of analyzing the study but not with other researchers
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 