<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/NCT01689519</url>
  </required_header>
  <id_info>
    <org_study_id>GO28141</org_study_id>
    <secondary_id>2012-003008-11</secondary_id>
    <nct_id>NCT01689519</nct_id>
  </id_info>
  <brief_title>A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma</brief_title>
  <acronym>coBRIM</acronym>
  <official_title>A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus GDC-0973 in Previously Untreated BRAF^600-Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hoffmann-La Roche</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hoffmann-La Roche</source>
  <brief_summary>
    <textblock>
      To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared&#xD;
      with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients&#xD;
      with unresectable locally advanced or metastatic melanoma, as measured by progression-free&#xD;
      survival (PFS), assessed by the study site investigator.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 8, 2013</start_date>
  <completion_date type="Actual">July 21, 2019</completion_date>
  <primary_completion_date type="Actual">May 9, 2014</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
    <description>Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
    <description>Overall survival was defined as the time from randomization until the date of death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With an Objective Response</measure>
    <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
    <description>An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
    <description>Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">495</enrollment>
  <condition>Malignant Melanoma</condition>
  <arm_group>
    <arm_group_label>Placebo + Vemurafenib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cobimetinib + Vemurafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo supplied as tablets</description>
    <arm_group_label>Placebo + Vemurafenib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vemurafenib</intervention_name>
    <description>Vemurafenib supplied as tablets</description>
    <arm_group_label>Cobimetinib + Vemurafenib</arm_group_label>
    <arm_group_label>Placebo + Vemurafenib</arm_group_label>
    <other_name>RO518426</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cobimetinib</intervention_name>
    <description>Cobimetinib supplied as tablets</description>
    <arm_group_label>Cobimetinib + Vemurafenib</arm_group_label>
    <other_name>GDC-0973</other_name>
    <other_name>RO5514041</other_name>
    <other_name>XL518</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants with histologically confirmed melanoma, either unresectable stage IIIc or&#xD;
             stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th&#xD;
             edition. Unresectability of stage IIIc disease must have confirmation from a surgical&#xD;
             oncologist&#xD;
&#xD;
          -  Participants must be naïve to treatment for locally advanced unresectable or&#xD;
             metastatic disease (ie, no prior systemic anti-cancer therapy for advanced disease;&#xD;
             stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed&#xD;
&#xD;
          -  Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue (archival&#xD;
             or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test&#xD;
&#xD;
          -  Measurable disease per RECIST v1.1&#xD;
&#xD;
          -  Eastern Clinical Oncology Group performance status of 0 or 1&#xD;
&#xD;
          -  Consent to provide archival for biomarker analyses&#xD;
&#xD;
          -  Consent to undergo tumor biopsies for biomarker analyses&#xD;
&#xD;
          -  Life expectancy greater than or equal to (≥) 12 weeks&#xD;
&#xD;
          -  Adequate hematologic and end organ function&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of prior rapidly accelerated fibrosarcoma or mitogen-activated protein kinase&#xD;
             pathway inhibitor treatment&#xD;
&#xD;
          -  Palliative radiotherapy within 14 days prior to the first dose of study treatment&#xD;
&#xD;
          -  Major surgery or traumatic injury within 14 days prior to first dose of study&#xD;
             treatment&#xD;
&#xD;
          -  Active malignancy other than melanoma that could potentially interfere with the&#xD;
             interpretation of efficacy measures. Participants with a previous malignancy within&#xD;
             the past 3 years are excluded except for participants with resected basal cell&#xD;
             carcinoma or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ&#xD;
             of the cervix, and carcinoma in-situ of the breast&#xD;
&#xD;
          -  History of or evidence of retinal pathology on ophthalmological examination that is&#xD;
             considered a risk factor for neurosensory retinal detachment, retinal vein occlusion,&#xD;
             or neovascular macular degeneration&#xD;
&#xD;
          -  Uncontrolled glaucoma with intraocular pressure&#xD;
&#xD;
          -  Serum cholesterol ≥ Grade 2&#xD;
&#xD;
          -  Hypertriglyceridemia ≥ Grade 2&#xD;
&#xD;
          -  Hyperglycemia (fasting) ≥ Grade 2&#xD;
&#xD;
          -  History of clinically significant cardiac dysfunction&#xD;
&#xD;
          -  Participants with active central nervous system (CNS) lesions (including carcinomatous&#xD;
             meningitis) are excluded. However, participants are eligible if:&#xD;
&#xD;
               1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND&#xD;
&#xD;
               2. There has been no evidence of clinical and radiographic disease progression in&#xD;
                  the CNS for ≥ 3 weeks after radiotherapy or surgery&#xD;
&#xD;
          -  Current severe, uncontrolled systemic disease&#xD;
&#xD;
          -  History of malabsorption or other condition that would interfere with absorption of&#xD;
             study drugs&#xD;
&#xD;
          -  Pregnant, lactating, or breast feeding women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>Hoffmann-La Roche</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Angeles Clinic and Research Institute - W LA Office</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90025</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California Davis Health System</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sutter Pacific Medical Foundation</name>
      <address>
        <city>Santa Rosa</city>
        <state>California</state>
        <zip>95403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Of Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Cancer Specialists - Broadway</name>
      <address>
        <city>Fort Myers</city>
        <state>Florida</state>
        <zip>33901</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Medical Center</name>
      <address>
        <city>Miami Beach</city>
        <state>Florida</state>
        <zip>33140</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Orlando Health Inc.</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern Center For Clinical Research</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uni of Kansas Medical Center; Dept of Neurology</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160-7314</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>U of L - Physicians Pulmonology; Dept of Neuroradiology and Dept of Diagnostic Radiology</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine; Dept of Medicine/Div of Medical Oncology</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dartmouth-Hitchcock Medical Center; Department of Medicine</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novant Health Oncology Specialists</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals of Cleveland</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Luke's University Health network</name>
      <address>
        <city>Bethlehem</city>
        <state>Pennsylvania</state>
        <zip>18015</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Thomas Jefferson University Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15261</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rhode Island Hospital; Investigational Services</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>2903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chris O'Brien Lifehouse</name>
      <address>
        <city>Camperdown</city>
        <state>New South Wales</state>
        <zip>2050</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lake Macquarie Private Hospital</name>
      <address>
        <city>Gateshead</city>
        <state>New South Wales</state>
        <zip>2290</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lismore Base Hospital; Cancer Care &amp; Haematology Unit</name>
      <address>
        <city>Lismore</city>
        <state>New South Wales</state>
        <zip>2480</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Melanoma Institute Australia</name>
      <address>
        <city>North Sydney</city>
        <state>New South Wales</state>
        <zip>2060</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Alexandra Hospital</name>
      <address>
        <city>Woolloongabba</city>
        <state>New South Wales</state>
        <zip>2050</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Darwin Hospital</name>
      <address>
        <city>Casuarina</city>
        <state>Northern Territory</state>
        <zip>0811</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Greenslopes Private Hospital</name>
      <address>
        <city>Greenslopes</city>
        <state>Queensland</state>
        <zip>4120</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Brisbane and Women's Hospital</name>
      <address>
        <city>Herston</city>
        <state>Queensland</state>
        <zip>4029</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Adelaide Hospital; Hepatology</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <zip>5000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ashford Cancer Centre</name>
      <address>
        <city>Ashford SA</city>
        <state>South Australia</state>
        <zip>5035</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Hobart Hospital</name>
      <address>
        <city>Hobart</city>
        <state>Tasmania</state>
        <zip>7000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Launceston General Hospital; Gastroenterology Research</name>
      <address>
        <city>Launceston</city>
        <state>Tasmania</state>
        <zip>7250</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peninsula and South Eastern Haematology and Oncology Group</name>
      <address>
        <city>Frankston</city>
        <state>Victoria</state>
        <zip>3199</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Austin Hospital</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peter MacCallum Cancer Centre-East Melbourne</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Alfred Hospital</name>
      <address>
        <city>Prahan</city>
        <state>Victoria</state>
        <zip>3181</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fiona Stanley Hospital</name>
      <address>
        <city>Murdoch</city>
        <state>Western Australia</state>
        <zip>6150</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ordensklinikum Linz Elisabethinen</name>
      <address>
        <city>Linz</city>
        <zip>4020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Landesklinikum St. Pölten</name>
      <address>
        <city>St. Pölten</city>
        <zip>3100</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medizinische Universität Wien</name>
      <address>
        <city>Wien</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Jules Bordet; Department of Medical Oncology</name>
      <address>
        <city>Bruxelles</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cliniques Universitaires St-Luc</name>
      <address>
        <city>Bruxelles</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UZ Antwerpen</name>
      <address>
        <city>Edegem</city>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jessa Zkh (Campus Virga Jesse)</name>
      <address>
        <city>Hasselt</city>
        <zip>3500</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Sart-Tilman</name>
      <address>
        <city>Liège</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AZ Delta (Campus Rumbeke)</name>
      <address>
        <city>Roeselare</city>
        <zip>8800</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>BC Cancer Agency Vancouver Island Cancer Centre</name>
      <address>
        <city>Victoria</city>
        <state>British Columbia</state>
        <zip>V8R 6V5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Juravinski Cancer Clinic; Department of Oncology</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8V 5C2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ottawa Hospital Cancer Center; General Campus</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 1C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toronto Sunnybrook Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Margaret Hospital; Department of Med Oncology</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>London Health Sciences Centre · Victoria Hospital;Department of Pediatrics</name>
      <address>
        <city>London</city>
        <state>Quebec</state>
        <zip>N6A 4G5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McGill University Health Centre/Glen Site / Royal Victoria Hospital</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H2W 1S6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Masarykuv onkologicky ustav</name>
      <address>
        <city>Brno</city>
        <zip>656 53</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultni nemocnice Hradec Kralove</name>
      <address>
        <city>Hradec Kralove</city>
        <zip>500 05</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultní nemocnice Olomouc</name>
      <address>
        <city>Olomouc</city>
        <zip>775 20</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultni nemocnice Ostrava</name>
      <address>
        <city>Ostrava - Poruba</city>
        <zip>708 52</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Multiscan s.r.o.</name>
      <address>
        <city>Pardubice</city>
        <zip>532 03</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemocnice Na Bulovce</name>
      <address>
        <city>Prague</city>
        <zip>180 01</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vseobecna fakultni nemocnice v Praze</name>
      <address>
        <city>Praha 2</city>
        <zip>128 08</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultni nemocnice Kralovske Vinohrady</name>
      <address>
        <city>Praha</city>
        <zip>100 34</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fakultni nemocnice Motol; Neurologicka klinika</name>
      <address>
        <city>Praha</city>
        <zip>150 06</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Groupe Hospitalier Saint André - Hôpital Saint André</name>
      <address>
        <city>Bordeaux</city>
        <zip>33075</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Ambroise Paré - Boulogne-Billancourt; Respiratory</name>
      <address>
        <city>Boulogne Billancourt</city>
        <zip>92104</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Clermont Ferrand - Hôpital d'Estaing</name>
      <address>
        <city>Clermont Ferrand cedex 1</city>
        <zip>63003</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Dijon - Hopital le Bocage</name>
      <address>
        <city>Dijon</city>
        <zip>21000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Grenoble - Albert Michallon</name>
      <address>
        <city>La Tronche</city>
        <zip>38700</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Claude Huriez - CHU Lille</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital de la Timone</name>
      <address>
        <city>Marseille</city>
        <zip>13005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Saint Eloi</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU NANTES - Hôtel Dieu; Pharmacy</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Nice - Hopital de l'Archet 2</name>
      <address>
        <city>Nice</city>
        <zip>06202</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Lyon Sud</name>
      <address>
        <city>Pierre Benite</city>
        <zip>69495</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Robert Debre; DERMATOLOGIE</name>
      <address>
        <city>Reims</city>
        <zip>51092</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Eugene Marquis; Service d'oncologie</name>
      <address>
        <city>Rennes</city>
        <zip>35042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Josef-Hospital; Studienambulanz</name>
      <address>
        <city>Bochum</city>
        <zip>44791</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Elbekliniken Buxtehude GmbH</name>
      <address>
        <city>Buxtehude</city>
        <zip>21614</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum &quot;Carl Gustav Carus&quot; der Technischen Universität Dresden</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helios Klinikum Erfurt</name>
      <address>
        <city>Erfurt</city>
        <zip>99089</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Essen</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Freiburg</name>
      <address>
        <city>Freiburg</city>
        <zip>79106</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie</name>
      <address>
        <city>Gera</city>
        <zip>07548</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin Göttingen</name>
      <address>
        <city>Göttingen</city>
        <zip>37075</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medizinische Hochschule Hannover</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Heidelberg</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Schleswig-Holstein - Campus Kiel; Klinik fuer Allgemeine Innere Medizin</name>
      <address>
        <city>Kiel</city>
        <zip>24105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Koeln; Hematology/Oncology</name>
      <address>
        <city>Koeln</city>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz</name>
      <address>
        <city>Mainz</city>
        <zip>55101</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Mannheim GmbH Universitätsklinikum</name>
      <address>
        <city>Mannheim</city>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fachklinik Hornheide</name>
      <address>
        <city>Muenster</city>
        <zip>48157</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum der Ludwigs-Maximilians-Universitaet Muenchen</name>
      <address>
        <city>München</city>
        <zip>80337</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Regensburg</name>
      <address>
        <city>Regensburg</city>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Tübingen</name>
      <address>
        <city>Tuebingen</city>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Wurzburg</name>
      <address>
        <city>Würzburg</city>
        <zip>97080</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Orszagos Onkologiai Intezet</name>
      <address>
        <city>Budapest</city>
        <zip>1122</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza</name>
      <address>
        <city>Gyula</city>
        <zip>5700</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Somogy Megyei Kaposi Mor Oktato Korhaz</name>
      <address>
        <city>Pecs</city>
        <zip>7624</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.</name>
      <address>
        <city>Szeged</city>
        <zip>6720</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Soroka Medical Center; Oncology Dept</name>
      <address>
        <city>Beer Sheva</city>
        <zip>8410100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Health Care Campus</name>
      <address>
        <city>Haifa</city>
        <zip>3109600</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HADASSAH UNIVERSITY HOSPITAL, EIN KAREM; Oncology</name>
      <address>
        <city>Jerusalem</city>
        <zip>9112000</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rabin Medical Center-Beilinson Campus;Hematology-Oncology</name>
      <address>
        <city>Petach Tikva</city>
        <zip>4941492</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chaim Sheba Medical Center</name>
      <address>
        <city>Ramat Gan</city>
        <zip>5265601</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tel Aviv Sourasky MC, Dana children's hospital;Oncology Division</name>
      <address>
        <city>Tel Aviv</city>
        <zip>6423906</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori Fondazione G. Pascale</name>
      <address>
        <city>Napoli</city>
        <state>Campania</state>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori</name>
      <address>
        <city>Meldola</city>
        <state>Emilia-Romagna</state>
        <zip>47014</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>A.O.U. Policlinico di Modena</name>
      <address>
        <city>Modena</city>
        <state>Emilia-Romagna</state>
        <zip>40124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori Regina Elena IRCCS</name>
      <address>
        <city>Roma</city>
        <state>Lazio</state>
        <zip>00144</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Nazionale per la Ricerca sul Cancro di Genova</name>
      <address>
        <city>Genova</city>
        <state>Liguria</state>
        <zip>16132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)</name>
      <address>
        <city>Bergamo</city>
        <state>Lombardia</state>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asst Degli Spedali Civili Di Brescia</name>
      <address>
        <city>Brescia</city>
        <state>Lombardia</state>
        <zip>25100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Nazionale dei Tumori</name>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Tumori Giovanni Paolo II IRCSS; Ospedale Oncologico Bari</name>
      <address>
        <city>Bari</city>
        <state>Puglia</state>
        <zip>70126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>A.O.U. Senese Policlinico Santa Maria Alle Scotte</name>
      <address>
        <city>Siena</city>
        <state>Toscana</state>
        <zip>53100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IOV - Istituto Oncologico Veneto IRCCS</name>
      <address>
        <city>Padova</city>
        <state>Veneto</state>
        <zip>35128</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amsterdam UMC Location VUMC</name>
      <address>
        <city>Amsterdam</city>
        <zip>1081 HV</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leids Universitair Medisch Centrum; Cardiology</name>
      <address>
        <city>Leiden</city>
        <zip>2333 ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maastricht University Medical Center</name>
      <address>
        <city>Maastricht</city>
        <zip>6229 HX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Auckland City Hospital</name>
      <address>
        <city>Auckland</city>
        <zip>1023</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Waikato Hospital</name>
      <address>
        <city>Hamilton</city>
        <zip>3248</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radiumhospitalet</name>
      <address>
        <city>Oslo</city>
        <zip>0379</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>TSBHI Altai Territorial oncological dispensary</name>
      <address>
        <city>Barnaul</city>
        <zip>656045</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>FSBSI &quot;N. N. Blokhin Russian Cancer Research Center&quot;</name>
      <address>
        <city>Moscow</city>
        <zip>115478</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moscow city oncology hospital #62 of Moscow Healthcare Department</name>
      <address>
        <city>Moscow</city>
        <zip>143423</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>BHI of Omsk region Clinical Oncology Dispensary</name>
      <address>
        <city>Omsk</city>
        <zip>644013</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pyatigorsky Oncologic Dispensary</name>
      <address>
        <city>Pyatigorsk</city>
        <zip>357524</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complexo Hospitalario Universitario de Santiago</name>
      <address>
        <city>Santiago de Compostela</city>
        <state>LA Coruña</state>
        <zip>15706</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica Universitaria de Navarra</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen Macarena</name>
      <address>
        <city>Seville</city>
        <state>Sevilla</state>
        <zip>41071</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínic i Provincial de Barcelona</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Madrid</city>
        <zip>28033</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital General Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <zip>46014</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Länssjukhuset Ryhov</name>
      <address>
        <city>Jönköping</city>
        <zip>551 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Skånes Universitetssjukhus</name>
      <address>
        <city>Lund</city>
        <zip>221 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sahlgrenska Sjukhuset</name>
      <address>
        <city>Mölnlycke</city>
        <zip>435 33</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Akademiska Sjukhuset</name>
      <address>
        <city>Uppsala</city>
        <zip>751 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Inselspital-Universitaetsspital Bern</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Graubuenden</name>
      <address>
        <city>Chur</city>
        <zip>7000</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bristol Haematology and Oncology Centre</name>
      <address>
        <city>Bristol</city>
        <zip>BS2 8ED</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Velindre Cancer Centre</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 2TL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Western General Hospital</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH4 2XU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beatson West of Scotland Cancer Centre</name>
      <address>
        <city>Glasgow</city>
        <zip>G12 0YN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Clatterbridge Cancer Centre NHS Foundation Trust</name>
      <address>
        <city>Liverpool</city>
        <zip>L7 8YA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barts and the London NHS Trust.</name>
      <address>
        <city>London</city>
        <zip>EC1A 7BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St George's Hospital; Courtyard Clinic</name>
      <address>
        <city>London</city>
        <zip>SW17 0QT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital - Fulham</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital - London</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Freeman Hospital</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <zip>NE7 7DN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nottingham University Hospitals; QMC Campus</name>
      <address>
        <city>Nottingham</city>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southampton General Hospital</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Cornwall Hospital</name>
      <address>
        <city>Truro</city>
        <zip>TR1 3LQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New Cross Hospital</name>
      <address>
        <city>Wolverhampton</city>
        <zip>WV10 0QP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Canada</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>New Zealand</country>
    <country>Norway</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
    <country>Turkey</country>
  </removed_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>September 18, 2012</study_first_submitted>
  <study_first_submitted_qc>September 18, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 21, 2012</study_first_posted>
  <results_first_submitted>July 1, 2015</results_first_submitted>
  <results_first_submitted_qc>October 1, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">October 30, 2015</results_first_posted>
  <last_update_submitted>April 1, 2022</last_update_submitted>
  <last_update_submitted_qc>April 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Zelboraf</keyword>
  <keyword>vemurafenib</keyword>
  <keyword>RG7204</keyword>
  <keyword>PLX4032</keyword>
  <keyword>Genentech MEK inhibitor</keyword>
  <keyword>Genentech BRAF inhibitor</keyword>
  <keyword>Roche MEK inhibitor</keyword>
  <keyword>Roche BRAF inhibitor</keyword>
  <keyword>RO5185426</keyword>
  <keyword>metastatic melanoma</keyword>
  <keyword>BRAF positive melanoma</keyword>
  <keyword>BRAF mutant melanoma</keyword>
  <keyword>advanced melanoma</keyword>
  <keyword>Genentech RAF inhibitor</keyword>
  <keyword>Roche RAF inhibitor</keyword>
  <keyword>BRAF V600E kinase inhibitor</keyword>
  <keyword>Oncogenic BRAF inhibitor</keyword>
  <keyword>BRAF kinase inhibitor</keyword>
  <keyword>GDC-0973</keyword>
  <keyword>XL518</keyword>
  <keyword>melanoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vemurafenib</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 20, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/19/NCT01689519/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Cobimetinib + Vemurafenib</title>
          <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
        </group>
        <group group_id="P2">
          <title>Placebo + Vemurafenib</title>
          <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Intent to Treat</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="247"/>
                <participants group_id="P2" count="248"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="247"/>
                <participants group_id="P2" count="248"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="157"/>
                <participants group_id="P2" count="167"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study terminated by Spon6sor</title>
              <participants_list>
                <participants group_id="P1" count="59"/>
                <participants group_id="P2" count="48"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Safety Population</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="248"/>
                <participants group_id="P2" count="245"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="248"/>
                <participants group_id="P2" count="245"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="158"/>
                <participants group_id="P2" count="165"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study Terminated By Sponsor</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
                <participants group_id="P2" count="47"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</population>
      <group_list>
        <group group_id="B1">
          <title>Cobimetinib + Vemurafenib</title>
          <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
        </group>
        <group group_id="B2">
          <title>Placebo + Vemurafenib</title>
          <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</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="247"/>
            <count group_id="B2" value="248"/>
            <count group_id="B3" value="495"/>
          </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="183"/>
                    <measurement group_id="B2" value="179"/>
                    <measurement group_id="B3" value="362"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="64"/>
                    <measurement group_id="B2" value="69"/>
                    <measurement group_id="B3" value="133"/>
                  </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="54.9" spread="14.0"/>
                    <measurement group_id="B2" value="55.3" spread="13.8"/>
                    <measurement group_id="B3" value="55.1" spread="13.9"/>
                  </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="101"/>
                    <measurement group_id="B2" value="108"/>
                    <measurement group_id="B3" value="209"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="146"/>
                    <measurement group_id="B2" value="140"/>
                    <measurement group_id="B3" value="286"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Count of Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than one race</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native Hawaiian or other Pacific Islande</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="227"/>
                    <measurement group_id="B2" value="235"/>
                    <measurement group_id="B3" value="462"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown or Not Reported</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Count of Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="213"/>
                    <measurement group_id="B2" value="223"/>
                    <measurement group_id="B3" value="436"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Stated</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression-free Survival</title>
        <description>Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.</description>
        <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
        <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib + Vemurafenib</title>
            <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + Vemurafenib</title>
            <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival</title>
          <description>Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.</description>
          <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</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="247"/>
                <count group_id="O2" value="248"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Primary Analysis: 9 May 2014</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.90" lower_limit="9.00" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                    <measurement group_id="O2" value="6.20" lower_limit="5.55" upper_limit="7.39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post hoc Efficacy Analysis: 16 January 2015</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.30" lower_limit="9.50" upper_limit="13.40"/>
                    <measurement group_id="O2" value="7.20" lower_limit="5.60" upper_limit="7.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Extended 5-Year Analysis: 21 July 2019</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.60" lower_limit="9.50" upper_limit="14.80"/>
                    <measurement group_id="O2" value="7.20" lower_limit="5.60" upper_limit="7.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Primary Analysis 9 May 2014</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0001</p_value>
            <p_value_desc>The analysis was stratified by geographic region and metastasis classification (disease stage).</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.51</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.39</ci_lower_limit>
            <ci_upper_limit>0.68</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Post hoc Efficacy Analysis: 16 January 2015</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>The analysis was stratified by geographic region and metastasis classification (disease stage).</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.58</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.46</ci_lower_limit>
            <ci_upper_limit>0.72</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Extended 5-Year Analysis: 21 July 2019</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>The analysis was stratified by geographic region and metastasis classification (disease stage).</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.65</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.53</ci_lower_limit>
            <ci_upper_limit>0.79</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall survival was defined as the time from randomization until the date of death from any cause.</description>
        <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
        <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib + Vemurafenib</title>
            <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + Vemurafenib</title>
            <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall survival was defined as the time from randomization until the date of death from any cause.</description>
          <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</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="247"/>
                <count group_id="O2" value="248"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Primary Analysis 9 May 2014</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post hoc Analysis 16 January 2015</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="20.70" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                    <measurement group_id="O2" value="17.00" lower_limit="15.00" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final Analysis 28 August 2015</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.30" lower_limit="20.3" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                    <measurement group_id="O2" value="17.40" lower_limit="15.00" upper_limit="19.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Extended 5-year Analysis 21 July 2019</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.50" lower_limit="20.30" upper_limit="28.80"/>
                    <measurement group_id="O2" value="17.40" lower_limit="15.00" upper_limit="19.80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Primary Analysis 9 May 2014</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0463</p_value>
            <p_value_desc>The analysis was stratified by geographic region and metastasis classification (disease stage).</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.645</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.42</ci_lower_limit>
            <ci_upper_limit>1.00</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Post hoc Analysis 16 January 2015</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0034</p_value>
            <p_value_desc>The analysis was stratified by geographic region and metastasis classification (disease stage).</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.65</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.49</ci_lower_limit>
            <ci_upper_limit>0.87</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Final Analysis 28 August 2015</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0050</p_value>
            <p_value_desc>The analysis was stratified by geographic region and metastasis classification (disease stage).</p_value_desc>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.70</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.55</ci_lower_limit>
            <ci_upper_limit>0.90</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With an Objective Response</title>
        <description>An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.</description>
        <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
        <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib + Vemurafenib</title>
            <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + Vemurafenib</title>
            <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With an Objective Response</title>
          <description>An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.</description>
          <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="247"/>
                <count group_id="O2" value="248"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Primary Analysis: 9 May 2014</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67.60" lower_limit="61.39" upper_limit="73.41"/>
                    <measurement group_id="O2" value="44.80" lower_limit="38.46" upper_limit="51.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post hoc Efficacy Analysis: 16 January 2015</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69.60" lower_limit="63.50" upper_limit="75.30"/>
                    <measurement group_id="O2" value="50.00" lower_limit="43.60" upper_limit="56.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Extended 5-Year Analysis: 21 July 2019</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69.60" lower_limit="63.49" upper_limit="75.31"/>
                    <measurement group_id="O2" value="49.60" lower_limit="43.21" upper_limit="55.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Primary Analysis: 9 May 2014</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Chi-squared</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>22.85</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>14.13</ci_lower_limit>
            <ci_upper_limit>31.58</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Post hoc Efficacy Analysis: 16 January 2015</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Chi-squared</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>19.6</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>11.0</ci_lower_limit>
            <ci_upper_limit>28.3</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Extended 5-Year Analysis: 21 July 2019</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Chi-squared</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>20.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>11.40</ci_lower_limit>
            <ci_upper_limit>28.70</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response</title>
        <description>Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.</description>
        <time_frame>Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)</time_frame>
        <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received. Only participants with an objective response were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib + Vemurafenib</title>
            <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + Vemurafenib</title>
            <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response</title>
          <description>Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.</description>
          <population>Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received. Only participants with an objective response were included in the analysis.</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="247"/>
                <count group_id="O2" value="248"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Primary Analysis: 9 May 2014</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="247"/>
                    <count group_id="O2" value="248"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="9.30" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                    <measurement group_id="O2" value="7.29" lower_limit="5.78" upper_limit="NA">NA = not estimable, could not be calculated due to too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Extended 5-Year Analysis: 21 July 2019</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="172"/>
                    <count group_id="O2" value="123"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.65" lower_limit="12.90" upper_limit="19.30"/>
                    <measurement group_id="O2" value="9.23" lower_limit="7.50" upper_limit="12.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months).</time_frame>
      <desc>1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem.&#xD;
All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.</desc>
      <group_list>
        <group group_id="E1">
          <title>Cobimetinib + Vemurafenib</title>
          <description>Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
        </group>
        <group group_id="E2">
          <title>Placebo + Vemurafenib</title>
          <description>Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (22.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="160" subjects_at_risk="247"/>
                <counts group_id="E2" subjects_affected="164" subjects_at_risk="248"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="105" subjects_at_risk="248"/>
                <counts group_id="E2" subjects_affected="71" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>ANAEMIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>ACUTE CORONARY SYNDROME</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ATRIAL FIBRILLATION</sub_title>
                <counts group_id="E1" events="8" subjects_affected="4" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CARDIAC ARREST</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CARDIAC FAILURE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CARDIAC TAMPONADE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MYOCARDIAL INFARCTION</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PERICARDIAL EFFUSION</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SUPRAVENTRICULAR TACHYCARDIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TACHYCARDIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>HYPERTHYROIDISM</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>CHORIORETINOPATHY</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>IRIDOCYCLITIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RETINAL DETACHMENT</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RETINAL HAEMORRHAGE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SEROUS RETINAL DETACHMENT</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>UVEITIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>ABDOMINAL PAIN</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>APHTHOUS ULCER</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>COLITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CONSTIPATION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DIARRHOEA</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSPHAGIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTRIC ANTRAL VASCULAR ECTASIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROINTESTINAL HAEMORRHAGE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROINTESTINAL PAIN</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROOESOPHAGEAL REFLUX DISEASE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>INGUINAL HERNIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>INTESTINAL OBSTRUCTION</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>INTESTINAL PERFORATION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MELAENA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>OBSTRUCTION GASTRIC</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PANCREATITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PERIODONTAL DISEASE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RECTAL POLYP</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SMALL INTESTINAL OBSTRUCTION</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>VOMITING</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>ASTHENIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CHEST PAIN</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DEATH</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FATIGUE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GAIT DISTURBANCE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MALAISE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PERIPHERAL SWELLING</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PYREXIA</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>CHOLECYSTITIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DRUG-INDUCED LIVER INJURY</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HEPATITIS ACUTE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>HYPERSENSITIVITY</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SARCOIDOSIS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>ABDOMINAL SEPSIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ANAL ABSCESS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ARTHRITIS BACTERIAL</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CAMPYLOBACTER GASTROENTERITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CELLULITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CLOSTRIDIUM DIFFICILE COLITIS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CLOSTRIDIUM DIFFICILE INFECTION</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DEVICE RELATED INFECTION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DIVERTICULITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ENTEROCOCCAL SEPSIS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ERYSIPELAS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROENTERITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROENTERITIS CLOSTRIDIAL</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROENTERITIS VIRAL</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROINTESTINAL BACTERIAL INFECTION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GENITOURINARY TRACT INFECTION</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GROIN ABSCESS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>INFECTION</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PNEUMONIA</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SEPSIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SEPTIC SHOCK</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TONSILLITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TUBERCULOSIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>URINARY TRACT INFECTION</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>VULVAL CELLULITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>WOUND INFECTION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>FACIAL BONES FRACTURE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FALL</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FEMORAL NECK FRACTURE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FRACTURE DISPLACEMENT</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>OVERDOSE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RIB FRACTURE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SKIN LACERATION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>THORACIC VERTEBRAL FRACTURE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TRAUMATIC HAEMATOMA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>UPPER LIMB FRACTURE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ALANINE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ASPARTATE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD ALKALINE PHOSPHATASE INCREASED</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD CREATINE PHOSPHOKINASE INCREASED</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD CREATININE INCREASED</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>EJECTION FRACTION DECREASED</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ELECTROCARDIOGRAM QT PROLONGED</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ELECTROCARDIOGRAM T WAVE ABNORMAL</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GAMMA-GLUTAMYLTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HAEMOGLOBIN DECREASED</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>LIPASE INCREASED</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>LIVER FUNCTION TEST INCREASED</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>DEHYDRATION</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DIABETES MELLITUS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPERNATRAEMIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPOKALAEMIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPONATRAEMIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TYPE 2 DIABETES MELLITUS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>ARTHRALGIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BACK PAIN</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BURSITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MUSCULAR WEAKNESS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MUSCULOSKELETAL CHEST PAIN</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MUSCULOSKELETAL PAIN</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MYALGIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PATHOLOGICAL FRACTURE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>POLYARTHRITIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RHABDOMYOLYSIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>ACANTHOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ADENOCARCINOMA OF COLON</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BENIGN NEOPLASM</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ENDOMETRIAL ADENOCARCINOMA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GASTROINTESTINAL TRACT ADENOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>KAPOSI'S SARCOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>KERATOACANTHOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>LUNG ADENOCARCINOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MALIGNANT MELANOMA IN SITU</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MUCINOUS BREAST CARCINOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PAPILLOMA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SQUAMOUS CELL CARCINOMA OF SKIN</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TRANSITIONAL CELL CARCINOMA</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TUMOUR HAEMORRHAGE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>TUMOUR PAIN</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>CEREBRAL HAEMORRHAGE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CEREBROVASCULAR ACCIDENT</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>COMA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DIZZINESS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSARTHRIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSGEUSIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FACIAL PARALYSIS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FACIAL PARESIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GENERALISED TONIC-CLONIC SEIZURE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HAEMORRHAGIC STROKE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HEADACHE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HEMIPARESIS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYDROCEPHALUS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ISCHAEMIC STROKE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MYASTHENIA GRAVIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PARAESTHESIA</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>POLYNEUROPATHY</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SEIZURE</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SUBARACHNOID HAEMORRHAGE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SYNCOPE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>MANIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>ACUTE KIDNEY INJURY</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DIABETIC NEPHROPATHY</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RENAL COLIC</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>URETEROLITHIASIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>CERVICAL POLYP</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>ATELECTASIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSPNOEA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>INTERSTITIAL LUNG DISEASE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PLEURAL EFFUSION</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PNEUMONITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PULMONARY EMBOLISM</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PULMONARY HAEMORRHAGE</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>DERMATITIS EXFOLIATIVE GENERALISED</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ERYTHEMA MULTIFORME</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ERYTHEMA NODOSUM</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPERKERATOSIS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PANNICULITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PHOTOSENSITIVITY REACTION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH GENERALISED</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH MACULAR</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH MACULO-PAPULAR</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="248"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH MORBILLIFORM</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>URTICARIA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>HYPERTENSION</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPERTENSIVE CRISIS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="248"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SUBGALEAL HAEMATOMA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>VASCULITIS</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>VENOUS THROMBOSIS LIMB</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="248"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0.05</frequency_threshold>
        <default_vocab>MedDRA (22.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="239" subjects_at_risk="248"/>
                <counts group_id="E2" subjects_affected="236" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>ANAEMIA</sub_title>
                <counts group_id="E1" events="76" subjects_affected="51" subjects_at_risk="248"/>
                <counts group_id="E2" events="26" subjects_affected="21" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>CHORIORETINOPATHY</sub_title>
                <counts group_id="E1" events="36" subjects_affected="30" subjects_at_risk="248"/>
                <counts group_id="E2" events="9" subjects_affected="4" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>VISION BLURRED</sub_title>
                <counts group_id="E1" events="37" subjects_affected="32" subjects_at_risk="248"/>
                <counts group_id="E2" events="9" subjects_affected="8" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>ABDOMINAL PAIN</sub_title>
                <counts group_id="E1" events="37" subjects_affected="30" subjects_at_risk="248"/>
                <counts group_id="E2" events="23" subjects_affected="20" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ABDOMINAL PAIN UPPER</sub_title>
                <counts group_id="E1" events="17" subjects_affected="15" subjects_at_risk="248"/>
                <counts group_id="E2" events="21" subjects_affected="18" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CONSTIPATION</sub_title>
                <counts group_id="E1" events="37" subjects_affected="27" subjects_at_risk="248"/>
                <counts group_id="E2" events="31" subjects_affected="29" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DIARRHOEA</sub_title>
                <counts group_id="E1" events="311" subjects_affected="151" subjects_at_risk="248"/>
                <counts group_id="E2" events="162" subjects_affected="84" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSPEPSIA</sub_title>
                <counts group_id="E1" events="22" subjects_affected="19" subjects_at_risk="248"/>
                <counts group_id="E2" events="15" subjects_affected="13" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>NAUSEA</sub_title>
                <counts group_id="E1" events="184" subjects_affected="108" subjects_at_risk="248"/>
                <counts group_id="E2" events="83" subjects_affected="67" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>STOMATITIS</sub_title>
                <counts group_id="E1" events="27" subjects_affected="17" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>VOMITING</sub_title>
                <counts group_id="E1" events="108" subjects_affected="69" subjects_at_risk="248"/>
                <counts group_id="E2" events="42" subjects_affected="33" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>ASTHENIA</sub_title>
                <counts group_id="E1" events="96" subjects_affected="51" subjects_at_risk="248"/>
                <counts group_id="E2" events="50" subjects_affected="43" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>CHILLS</sub_title>
                <counts group_id="E1" events="28" subjects_affected="25" subjects_at_risk="248"/>
                <counts group_id="E2" events="17" subjects_affected="14" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FATIGUE</sub_title>
                <counts group_id="E1" events="137" subjects_affected="93" subjects_at_risk="248"/>
                <counts group_id="E2" events="99" subjects_affected="83" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>OEDEMA PERIPHERAL</sub_title>
                <counts group_id="E1" events="49" subjects_affected="38" subjects_at_risk="248"/>
                <counts group_id="E2" events="32" subjects_affected="28" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PYREXIA</sub_title>
                <counts group_id="E1" events="130" subjects_affected="77" subjects_at_risk="248"/>
                <counts group_id="E2" events="77" subjects_affected="60" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>CONJUNCTIVITIS</sub_title>
                <counts group_id="E1" events="19" subjects_affected="18" subjects_at_risk="248"/>
                <counts group_id="E2" events="10" subjects_affected="8" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>FOLLICULITIS</sub_title>
                <counts group_id="E1" events="22" subjects_affected="19" subjects_at_risk="248"/>
                <counts group_id="E2" events="15" subjects_affected="12" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>NASOPHARYNGITIS</sub_title>
                <counts group_id="E1" events="29" subjects_affected="23" subjects_at_risk="248"/>
                <counts group_id="E2" events="21" subjects_affected="18" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>UPPER RESPIRATORY TRACT INFECTION</sub_title>
                <counts group_id="E1" events="18" subjects_affected="14" subjects_at_risk="248"/>
                <counts group_id="E2" events="15" subjects_affected="11" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>URINARY TRACT INFECTION</sub_title>
                <counts group_id="E1" events="25" subjects_affected="17" subjects_at_risk="248"/>
                <counts group_id="E2" events="13" subjects_affected="11" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>SUNBURN</sub_title>
                <counts group_id="E1" events="60" subjects_affected="37" subjects_at_risk="248"/>
                <counts group_id="E2" events="68" subjects_affected="45" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ALANINE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" events="94" subjects_affected="65" subjects_at_risk="248"/>
                <counts group_id="E2" events="48" subjects_affected="44" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ASPARTATE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" events="87" subjects_affected="64" subjects_at_risk="248"/>
                <counts group_id="E2" events="30" subjects_affected="29" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD ALKALINE PHOSPHATASE INCREASED</sub_title>
                <counts group_id="E1" events="67" subjects_affected="46" subjects_at_risk="248"/>
                <counts group_id="E2" events="30" subjects_affected="26" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD BILIRUBIN INCREASED</sub_title>
                <counts group_id="E1" events="29" subjects_affected="20" subjects_at_risk="248"/>
                <counts group_id="E2" events="22" subjects_affected="17" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD CHOLESTEROL INCREASED</sub_title>
                <counts group_id="E1" events="19" subjects_affected="16" subjects_at_risk="248"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD CREATINE PHOSPHOKINASE INCREASED</sub_title>
                <counts group_id="E1" events="171" subjects_affected="90" subjects_at_risk="248"/>
                <counts group_id="E2" events="13" subjects_affected="10" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD CREATININE INCREASED</sub_title>
                <counts group_id="E1" events="59" subjects_affected="45" subjects_at_risk="248"/>
                <counts group_id="E2" events="25" subjects_affected="20" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BLOOD LACTATE DEHYDROGENASE INCREASED</sub_title>
                <counts group_id="E1" events="30" subjects_affected="15" subjects_at_risk="248"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>EJECTION FRACTION DECREASED</sub_title>
                <counts group_id="E1" events="46" subjects_affected="31" subjects_at_risk="248"/>
                <counts group_id="E2" events="13" subjects_affected="12" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ELECTROCARDIOGRAM QT PROLONGED</sub_title>
                <counts group_id="E1" events="15" subjects_affected="12" subjects_at_risk="248"/>
                <counts group_id="E2" events="19" subjects_affected="13" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>GAMMA-GLUTAMYLTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" events="82" subjects_affected="57" subjects_at_risk="248"/>
                <counts group_id="E2" events="61" subjects_affected="45" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>WEIGHT DECREASED</sub_title>
                <counts group_id="E1" events="20" subjects_affected="18" subjects_at_risk="248"/>
                <counts group_id="E2" events="17" subjects_affected="14" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>DECREASED APPETITE</sub_title>
                <counts group_id="E1" events="75" subjects_affected="55" subjects_at_risk="248"/>
                <counts group_id="E2" events="55" subjects_affected="50" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPONATRAEMIA</sub_title>
                <counts group_id="E1" events="19" subjects_affected="13" subjects_at_risk="248"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>ARTHRALGIA</sub_title>
                <counts group_id="E1" events="172" subjects_affected="96" subjects_at_risk="248"/>
                <counts group_id="E2" events="179" subjects_affected="105" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>BACK PAIN</sub_title>
                <counts group_id="E1" events="30" subjects_affected="21" subjects_at_risk="248"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MUSCULOSKELETAL PAIN</sub_title>
                <counts group_id="E1" events="18" subjects_affected="17" subjects_at_risk="248"/>
                <counts group_id="E2" events="19" subjects_affected="16" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MYALGIA</sub_title>
                <counts group_id="E1" events="53" subjects_affected="41" subjects_at_risk="248"/>
                <counts group_id="E2" events="37" subjects_affected="33" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PAIN IN EXTREMITY</sub_title>
                <counts group_id="E1" events="51" subjects_affected="32" subjects_at_risk="248"/>
                <counts group_id="E2" events="54" subjects_affected="40" subjects_at_risk="245"/>
              </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" events="33" subjects_affected="16" subjects_at_risk="248"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>KERATOACANTHOMA</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="248"/>
                <counts group_id="E2" events="26" subjects_affected="20" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>MELANOCYTIC NAEVUS</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="248"/>
                <counts group_id="E2" events="26" subjects_affected="17" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SEBORRHOEIC KERATOSIS</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="248"/>
                <counts group_id="E2" events="24" subjects_affected="21" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SKIN PAPILLOMA</sub_title>
                <counts group_id="E1" events="26" subjects_affected="18" subjects_at_risk="248"/>
                <counts group_id="E2" events="36" subjects_affected="30" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SQUAMOUS CELL CARCINOMA OF SKIN</sub_title>
                <counts group_id="E1" events="25" subjects_affected="10" subjects_at_risk="248"/>
                <counts group_id="E2" events="66" subjects_affected="33" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>DIZZINESS</sub_title>
                <counts group_id="E1" events="18" subjects_affected="18" subjects_at_risk="248"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSGEUSIA</sub_title>
                <counts group_id="E1" events="29" subjects_affected="27" subjects_at_risk="248"/>
                <counts group_id="E2" events="17" subjects_affected="16" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HEADACHE</sub_title>
                <counts group_id="E1" events="76" subjects_affected="50" subjects_at_risk="248"/>
                <counts group_id="E2" events="50" subjects_affected="41" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>ANXIETY</sub_title>
                <counts group_id="E1" events="18" subjects_affected="16" subjects_at_risk="248"/>
                <counts group_id="E2" events="12" subjects_affected="11" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DEPRESSION</sub_title>
                <counts group_id="E1" events="17" subjects_affected="15" subjects_at_risk="248"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>INSOMNIA</sub_title>
                <counts group_id="E1" events="24" subjects_affected="19" subjects_at_risk="248"/>
                <counts group_id="E2" events="31" subjects_affected="27" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>COUGH</sub_title>
                <counts group_id="E1" events="36" subjects_affected="28" subjects_at_risk="248"/>
                <counts group_id="E2" events="37" subjects_affected="32" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DYSPNOEA</sub_title>
                <counts group_id="E1" events="26" subjects_affected="19" subjects_at_risk="248"/>
                <counts group_id="E2" events="23" subjects_affected="19" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>OROPHARYNGEAL PAIN</sub_title>
                <counts group_id="E1" events="20" subjects_affected="19" subjects_at_risk="248"/>
                <counts group_id="E2" events="28" subjects_affected="22" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>ACTINIC KERATOSIS</sub_title>
                <counts group_id="E1" events="32" subjects_affected="13" subjects_at_risk="248"/>
                <counts group_id="E2" events="31" subjects_affected="27" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ALOPECIA</sub_title>
                <counts group_id="E1" events="44" subjects_affected="42" subjects_at_risk="248"/>
                <counts group_id="E2" events="78" subjects_affected="75" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DERMATITIS ACNEIFORM</sub_title>
                <counts group_id="E1" events="47" subjects_affected="37" subjects_at_risk="248"/>
                <counts group_id="E2" events="26" subjects_affected="22" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>DRY SKIN</sub_title>
                <counts group_id="E1" events="40" subjects_affected="37" subjects_at_risk="248"/>
                <counts group_id="E2" events="46" subjects_affected="42" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>ERYTHEMA</sub_title>
                <counts group_id="E1" events="56" subjects_affected="32" subjects_at_risk="248"/>
                <counts group_id="E2" events="57" subjects_affected="36" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>HYPERKERATOSIS</sub_title>
                <counts group_id="E1" events="39" subjects_affected="31" subjects_at_risk="248"/>
                <counts group_id="E2" events="130" subjects_affected="74" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>KERATOSIS PILARIS</sub_title>
                <counts group_id="E1" events="14" subjects_affected="13" subjects_at_risk="248"/>
                <counts group_id="E2" events="30" subjects_affected="26" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME</sub_title>
                <counts group_id="E1" events="23" subjects_affected="18" subjects_at_risk="248"/>
                <counts group_id="E2" events="10" subjects_affected="9" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PHOTOSENSITIVITY REACTION</sub_title>
                <counts group_id="E1" events="119" subjects_affected="86" subjects_at_risk="248"/>
                <counts group_id="E2" events="58" subjects_affected="48" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>PRURITUS</sub_title>
                <counts group_id="E1" events="85" subjects_affected="51" subjects_at_risk="248"/>
                <counts group_id="E2" events="54" subjects_affected="48" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH</sub_title>
                <counts group_id="E1" events="158" subjects_affected="101" subjects_at_risk="248"/>
                <counts group_id="E2" events="121" subjects_affected="97" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>RASH MACULO-PAPULAR</sub_title>
                <counts group_id="E1" events="61" subjects_affected="37" subjects_at_risk="248"/>
                <counts group_id="E2" events="47" subjects_affected="37" subjects_at_risk="245"/>
              </event>
              <event>
                <sub_title>SOLAR DERMATITIS</sub_title>
                <counts group_id="E1" events="34" subjects_affected="18" subjects_at_risk="248"/>
                <counts group_id="E2" events="23" subjects_affected="14" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>HYPERTENSION</sub_title>
                <counts group_id="E1" events="60" subjects_affected="50" subjects_at_risk="248"/>
                <counts group_id="E2" events="33" subjects_affected="30" subjects_at_risk="245"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Medical Communications</name_or_title>
      <organization>Hoffmann-La Roche</organization>
      <phone>800 821-8590</phone>
    </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/NCT01689519
org study id: GO28141
secondary id: 2012-003008-11
nct id: NCT01689519
lead sponsor: 
To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared
      with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients
      with unresectable locally advanced or metastatic melanoma, as measured by progression-free
      survival (PFS), assessed by the study site investigator.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Progression-free Survival
time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
description: Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
measure: Overall Survival
time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
description: Overall survival was defined as the time from randomization until the date of death from any cause.
measure: Percentage of Participants With an Objective Response
time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
description: An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.
measure: Duration of Response
time frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
description: Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
arm group label: Placebo + Vemurafenib
arm group type: Active Comparator
description: Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
arm group label: Cobimetinib + Vemurafenib
arm group type: Experimental
description: Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
intervention type: Drug
intervention name: Placebo
description: Placebo supplied as tablets
arm group label: Placebo + Vemurafenib
intervention type: Drug
intervention name: Vemurafenib
description: Vemurafenib supplied as tablets
arm group label: Cobimetinib + Vemurafenib
arm group label: Placebo + Vemurafenib
other name: RO518426
intervention type: Drug
intervention name: Cobimetinib
description: Cobimetinib supplied as tablets
arm group label: Cobimetinib + Vemurafenib
other name: GDC-0973
other name: RO5514041
other name: XL518
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Trials
role: Study Director
affiliation: Hoffmann-La Roche
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country: Australia
country: Austria
country: Belgium
country: Canada
country: Czechia
country: France
country: Germany
country: Hungary
country: Israel
country: Italy
country: Netherlands
country: New Zealand
country: Norway
country: Russian Federation
country: Spain
country: Sweden
country: Switzerland
country: United Kingdom
country: United States
country: Czech Republic
country: Turkey
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Vemurafenib
provided document: 
participant flow: 
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reported events: 
certain agreements: 
point of contact: 