<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/NCT01682083</url>
  </required_header>
  <id_info>
    <org_study_id>115532</org_study_id>
    <secondary_id>2012-001266-15</secondary_id>
    <secondary_id>CDRB436F2301</secondary_id>
    <nct_id>NCT01682083</nct_id>
  </id_info>
  <brief_title>Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).</brief_title>
  <acronym>COMBI-AD</acronym>
  <official_title>COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination&#xD;
      with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical&#xD;
      resection. Patients with completely resected, histologically confirmed, BRAF V600E/K&#xD;
      mutation-positive, high-risk [Stage IIIa (lymph node metastasis &gt;1 mm), IIIb or IIIc]&#xD;
      cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either&#xD;
      dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD])&#xD;
      combination therapy or two placebos for 12 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a two-arm, randomized, double-blind, multi-center, international phase III study of&#xD;
      dabrafenib in combination with trametinib versus two matching placebos in the adjuvant&#xD;
      treatment of melanoma after surgical resection. Patients with completely resected,&#xD;
      histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node&#xD;
      metastasis &gt;1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. Subjects&#xD;
      were randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and&#xD;
      trametinib (2 mg once daily [QD]). None of the patients had undergone previous systemic&#xD;
      anticancer treatment or radiotherapy for melanoma. All the patients had undergone completion&#xD;
      lymphadenectomy with no clinical or radiographic evidence of residual regional node disease&#xD;
      within 12 weeks before randomization, had recovered from definitive surgery, and had an&#xD;
      Eastern Cooperative Oncology Group performance status of 0 or 1. BRAF V600 mutation status&#xD;
      was confirmed in primary-tumor or lymph-node tissue by a central reference laboratory. All&#xD;
      the patients provided written informed consent.&#xD;
&#xD;
      The primary end point was recurrence-free survival, Overall survival, as the key secondary&#xD;
      end point, was to be tested in a hierarchical manner only if the primary end point met the&#xD;
      criteria for significance. The overall survival analysis used a preplanned three-look&#xD;
      Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary, which was used to&#xD;
      determine the significance threshold for the first interim overall survival analysis&#xD;
      (two-sided P=0.000019).&#xD;
&#xD;
      Disease assessments included clinical examination and imaging by means of computed&#xD;
      tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months during&#xD;
      the first 24 months, then every 6 months until disease recurrence or the completion of the&#xD;
      trial. Follow-up for survival began after recurrence and continued through the end of the&#xD;
      trial. Adverse events and laboratory values were assessed at screening, on the date of&#xD;
      randomization, at least once per month through month 12, and at every visit for&#xD;
      disease-recurrence assessment after month 12. Adverse events and laboratory values were&#xD;
      graded according to the Common Terminology Criteria for Adverse Events, version 4.0.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 8, 2013</start_date>
  <completion_date type="Actual">July 31, 2023</completion_date>
  <primary_completion_date type="Actual">June 30, 2017</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Relapse-free Survival (RFS)</measure>
    <time_frame>Approximately 3.5 years</time_frame>
    <description>Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>approximately 3.5 years</time_frame>
    <description>Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distant Metastasis-free Survival</measure>
    <time_frame>approximately 3.5 years</time_frame>
    <description>Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Freedom From Relapse</measure>
    <time_frame>approximately 3.5 years</time_frame>
    <description>Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">870</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Dabrafenib and trametinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dabrafenib and trametinib placebos</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects received matching placebos orally for 12 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabrafenib</intervention_name>
    <description>Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)</description>
    <arm_group_label>Dabrafenib and trametinib</arm_group_label>
    <other_name>GSK2118436</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trametinib</intervention_name>
    <description>Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)</description>
    <arm_group_label>Dabrafenib and trametinib</arm_group_label>
    <other_name>GSK1120212</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment</description>
    <arm_group_label>Dabrafenib and trametinib placebos</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more&#xD;
             than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive&#xD;
             by a central laboratory. Patients presenting with initial resectable lymph node&#xD;
             recurrence after a diagnosis of Stage I or II melanoma are eligible.&#xD;
&#xD;
          -  Surgically rendered free of disease no more than 12 weeks before randomization.&#xD;
&#xD;
          -  Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling&#xD;
             drains).&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.&#xD;
&#xD;
          -  Adequate hematologic, hepatic, renal and cardiac function.&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  Known mucosal or ocular melanoma or the presence of unresectable in-transit&#xD;
             metastases.&#xD;
&#xD;
          -  Evidence of distant metastatic disease.&#xD;
&#xD;
          -  Prior systemic anti-cancer treatment and radiotherapy for melanoma; prior surgery for&#xD;
             melanoma is allowed.&#xD;
&#xD;
          -  History of another malignancy or concurrent malignancy including prior malignant&#xD;
             melanoma. Exceptions to this include: Patients who have been disease-free for 5 years&#xD;
             or patients with a history completely resected non-melanoma skin cancer or&#xD;
             successfully treated in situ carcinoma are eligible, for example cervical cancer in&#xD;
             situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary&#xD;
             melanomas, or other malignancies for which the patient has been disease free for &gt; 5&#xD;
             years.&#xD;
&#xD;
          -  History or current evidence of cardiovascular risk.&#xD;
&#xD;
          -  History or current evidence of retinal vein occlusion (RVO) or central serous&#xD;
             retinopathy (CSR)&#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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35243</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85719</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Farmington</city>
        <state>Connecticut</state>
        <zip>06030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Fort Myers</city>
        <state>Florida</state>
        <zip>33916</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lake Worth</city>
        <state>Florida</state>
        <zip>33461</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Stuart</city>
        <state>Florida</state>
        <zip>34994</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30341</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21237</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lutherville-Timonium</city>
        <state>Maryland</state>
        <zip>21093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48019</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Morristown</city>
        <state>New Jersey</state>
        <zip>07960</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232-5536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <zip>84107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Capital Federal</city>
        <state>Buenos Aires</state>
        <zip>C1426ANZ</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ciudad Autonoma de Buenos Aires</city>
        <state>Buenos Aires</state>
        <zip>C1050AAK</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Viedma</city>
        <state>Río Negro</state>
        <zip>R8500ACE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rosario</city>
        <state>Santa Fe</state>
        <zip>S2000KZE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ciudad Autonoma de Buenos Aires</city>
        <zip>C1025ABH</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ciudad Autonoma de Buenos Aires</city>
        <zip>C1121ABE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Santa Fe</city>
        <zip>3000</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Gateshead</city>
        <state>New South Wales</state>
        <zip>2290</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>North Sydney</city>
        <state>New South Wales</state>
        <zip>2060</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tweed Heads</city>
        <state>New South Wales</state>
        <zip>2485</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Westmead</city>
        <state>New South Wales</state>
        <zip>2145</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Greenslopes</city>
        <state>Queensland</state>
        <zip>4120</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milton</city>
        <state>Queensland</state>
        <zip>4064</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Woolloongabba</city>
        <state>Queensland</state>
        <zip>4102</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <zip>5000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Box Hill</city>
        <state>Victoria</state>
        <zip>3128</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3004</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nedlands</city>
        <state>Western Australia</state>
        <zip>6009</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Graz</city>
        <zip>8036</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Innsbruck</city>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Linz</city>
        <zip>A-4010</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Salzburg</city>
        <zip>A-5020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wels</city>
        <zip>A-4600</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wien</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wien</city>
        <zip>A-1030</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wien</city>
        <zip>A-1220</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Brussels</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Liege</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wilrijk</city>
        <zip>2610</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Goiania</city>
        <state>Goiás</state>
        <zip>74605-030</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Curitiba</city>
        <state>Paraná</state>
        <zip>81520-060</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ijui</city>
        <state>Rio Grande Do Sul</state>
        <zip>98700-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rio De Janeiro</city>
        <zip>22 260-020</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>São Paulo</city>
        <zip>01323-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8V 5C2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Oshawa</city>
        <state>Ontario</state>
        <zip>L1G 2B9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2W 1S6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Quebec</city>
        <zip>G1R 2J6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Brno</city>
        <zip>656 53</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hradec Kralove</city>
        <zip>500 05</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Olomouc</city>
        <zip>775 20</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Praha 10</city>
        <zip>100 34</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Praha 2</city>
        <zip>128 08</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Zlin</city>
        <zip>76275</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Arhus C</city>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Herlev</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Odense</city>
        <zip>5000 C</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bordeaux</city>
        <zip>33075</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Boulogne-Billancourt</city>
        <zip>92100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Brest cedex</city>
        <zip>29609</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Grenoble</city>
        <zip>38043</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Marseille cedex 5</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Montpellier cedex 5</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nice</city>
        <zip>06202</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Paris Cedex 10</city>
        <zip>75475</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Paris</city>
        <zip>75006</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pierre-Benite cedex</city>
        <zip>69495</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Reims Cedex</city>
        <zip>51092</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rennes Cedex</city>
        <zip>35042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Toulouse cedex 9</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tours Cedex 9</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Villejuif cedex</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Freiburg</city>
        <state>Baden-Wuerttemberg</state>
        <zip>79104</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Heidelberg</city>
        <state>Baden-Wuerttemberg</state>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Heilbronn</city>
        <state>Baden-Wuerttemberg</state>
        <zip>74078</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Mannheim</city>
        <state>Baden-Wuerttemberg</state>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tuebingen</city>
        <state>Baden-Wuerttemberg</state>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ulm</city>
        <state>Baden-Wuerttemberg</state>
        <zip>89081</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Muenchen</city>
        <state>Bayern</state>
        <zip>80337</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Muenchen</city>
        <state>Bayern</state>
        <zip>80804</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nuernberg</city>
        <state>Bayern</state>
        <zip>90419</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Regensburg</city>
        <state>Bayern</state>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wuerzburg</city>
        <state>Bayern</state>
        <zip>97080</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Darmstadt</city>
        <state>Hessen</state>
        <zip>64297</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kassel</city>
        <state>Hessen</state>
        <zip>34125</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Marburg</city>
        <state>Hessen</state>
        <zip>35043</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wiesbaden</city>
        <state>Hessen</state>
        <zip>65199</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Schwerin</city>
        <state>Mecklenburg-Vorpommern</state>
        <zip>19049</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Buxtehude</city>
        <state>Niedersachsen</state>
        <zip>21614</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hannover</city>
        <state>Niedersachsen</state>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Aachen</city>
        <state>Nordrhein-Westfalen</state>
        <zip>52074</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bochum</city>
        <state>Nordrhein-Westfalen</state>
        <zip>44791</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bonn</city>
        <state>Nordrhein-Westfalen</state>
        <zip>53127</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Essen</city>
        <state>Nordrhein-Westfalen</state>
        <zip>45122</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Koeln</city>
        <state>Nordrhein-Westfalen</state>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Muenster</city>
        <state>Nordrhein-Westfalen</state>
        <zip>48149</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Mainz</city>
        <state>Rheinland-Pfalz</state>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Homburg</city>
        <state>Saarland</state>
        <zip>66421</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Magdeburg</city>
        <state>Sachsen-Anhalt</state>
        <zip>39120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Quedlinburg</city>
        <state>Sachsen-Anhalt</state>
        <zip>06484</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kiel</city>
        <state>Schleswig-Holstein</state>
        <zip>24105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Luebeck</city>
        <state>Schleswig-Holstein</state>
        <zip>23538</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Erfurt</city>
        <state>Thueringen</state>
        <zip>99089</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Gera</city>
        <state>Thueringen</state>
        <zip>07548</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berlin</city>
        <zip>10117</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berlin</city>
        <zip>10249</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berlin</city>
        <zip>13585</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Athens</city>
        <zip>11527</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Thessaloniki</city>
        <zip>54622</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Thessaloniki</city>
        <zip>564 29</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Jerusalem</city>
        <zip>91120</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ramat Gan</city>
        <zip>52621</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Roma</city>
        <state>Lazio</state>
        <zip>00167</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Genova</city>
        <state>Liguria</state>
        <zip>16132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bergamo</city>
        <state>Lombardia</state>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20141</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Candiolo</city>
        <state>Piemonte</state>
        <zip>10060</zip>
        <country>Italy</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pisa</city>
        <state>Toscana</state>
        <zip>56126</zip>
        <country>Italy</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Padova</city>
        <state>Veneto</state>
        <zip>35128</zip>
        <country>Italy</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Shizuoka</city>
        <zip>411-8777</zip>
        <country>Japan</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tokyo</city>
        <zip>104-0045</zip>
        <country>Japan</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066 CX</zip>
        <country>Netherlands</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Amsterdam</city>
        <zip>1081 HV</zip>
        <country>Netherlands</country>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Groningen</city>
        <zip>9713 GZ</zip>
        <country>Netherlands</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Leeuwarden</city>
        <zip>8934 AD</zip>
        <country>Netherlands</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Maastricht</city>
        <zip>6229 HX</zip>
        <country>Netherlands</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nijmegen</city>
        <zip>6525 GA</zip>
        <country>Netherlands</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rotterdam</city>
        <zip>3015 GD</zip>
        <country>Netherlands</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Auckland</city>
        <zip>0622</zip>
        <country>New Zealand</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Alesund</city>
        <zip>6026</zip>
        <country>Norway</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Oslo</city>
        <zip>0310</zip>
        <country>Norway</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Gdansk</city>
        <zip>80-215</zip>
        <country>Poland</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Konin</city>
        <zip>62-500</zip>
        <country>Poland</country>
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  <location>
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      <address>
        <city>Poznan</city>
        <zip>60-693</zip>
        <country>Poland</country>
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  <location>
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      <address>
        <city>Warszawa</city>
        <zip>02-781</zip>
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  <location>
    <facility>
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      <address>
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        <zip>04-125</zip>
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  <location>
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      <address>
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        <zip>454087</zip>
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  <location>
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      <address>
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        <zip>115478</zip>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
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        <zip>143423</zip>
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  <location>
    <facility>
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      <address>
        <city>Ryazan</city>
        <zip>390011</zip>
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  <location>
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      <address>
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  <location>
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      <name>Novartis Investigative Site</name>
      <address>
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        <zip>197758</zip>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>St. Petersburg</city>
        <country>Russian Federation</country>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Volgograd</city>
        <zip>400138</zip>
        <country>Russian Federation</country>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Badalona</city>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Cartagena</city>
        <zip>30202</zip>
        <country>Spain</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Las Palmas De Gran Canaria</city>
        <zip>35016</zip>
        <country>Spain</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Malaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Palma de Mallorca</city>
        <zip>07198</zip>
        <country>Spain</country>
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    </facility>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pamplona</city>
        <zip>31008</zip>
        <country>Spain</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Sebastian</city>
        <zip>20014</zip>
        <country>Spain</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Santander</city>
        <zip>39008</zip>
        <country>Spain</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sevilla</city>
        <zip>41014</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Valencia</city>
        <zip>46014</zip>
        <country>Spain</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Goteborg</city>
        <zip>SE-413 45</zip>
        <country>Sweden</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lund</city>
        <zip>SE-221 85</zip>
        <country>Sweden</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Stockholm</city>
        <zip>SE-171 76</zip>
        <country>Sweden</country>
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    </facility>
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  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Uppsala</city>
        <zip>SE-751 85</zip>
        <country>Sweden</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Basel</city>
        <zip>4031</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Chur</city>
        <zip>7000</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Zurich</city>
        <zip>8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Taichung</city>
        <zip>404</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Taoyuan</city>
        <zip>333</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Northwood</city>
        <state>Middlesex</state>
        <zip>HA6 2RN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Exeter</city>
        <zip>EX2 5DW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Glasgow</city>
        <zip>G12 0YN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Guildford</city>
        <zip>GU2 7XX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Leeds</city>
        <zip>LS9 7TF</zip>
        <country>United Kingdom</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>London</city>
        <zip>NW3 2QG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>London</city>
        <zip>W1G 6AD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Manchester</city>
        <zip>M20 4BX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <zip>NE7 7DN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Norwich</city>
        <zip>NR4 7UY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Preston</city>
        <zip>PR2 9HT</zip>
        <country>United Kingdom</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Brazil</country>
    <country>Canada</country>
    <country>Czechia</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Netherlands</country>
    <country>New Zealand</country>
    <country>Norway</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Switzerland</country>
    <country>Taiwan</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
    <country>Finland</country>
  </removed_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>September 6, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <results_first_submitted>May 29, 2018</results_first_submitted>
  <results_first_submitted_qc>August 28, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">September 26, 2018</results_first_posted>
  <disposition_first_submitted>March 30, 2018</disposition_first_submitted>
  <disposition_first_submitted_qc>March 30, 2018</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">April 3, 2018</disposition_first_posted>
  <last_update_submitted>August 16, 2023</last_update_submitted>
  <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MEK inhibitor</keyword>
  <keyword>trametinib</keyword>
  <keyword>Oncology</keyword>
  <keyword>adjuvant melanoma</keyword>
  <keyword>dabrafenib</keyword>
  <keyword>dabrafenib and trametinib combination therapy</keyword>
  <keyword>BRAF mutation-positive melanoma</keyword>
  <keyword>BRAF inhibitor</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>Trametinib</mesh_term>
    <mesh_term>Dabrafenib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com</ipd_description>
  </patient_data>
  <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>May 31, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT01682083/Prot_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 31, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT01682083/SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study was conducted in 169 centers across 25 countries. Results reported have the data cut-off as of 30 June 2017.</recruitment_details>
      <pre_assignment_details>Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIA (lymph node metastasis &amp;gt;1 mm), IIIB, or IIIC] cutaneous melanoma.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Dabrafenib and Trametinib Combination Therapy</title>
          <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
        </group>
        <group group_id="P2">
          <title>Dabrafenib and Trametinib Placebos</title>
          <description>Subjects received matching placebos orally for 12 months</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="438"/>
                <participants group_id="P2" count="432"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="331">Ongoing patients at the time of data cut-off. 3 patients were untreated</participants>
                <participants group_id="P2" count="277">Ongoing patients at the time of data cut-off.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="107"/>
                <participants group_id="P2" count="155"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
                <participants group_id="P2" count="40"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
                <participants group_id="P2" count="93"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The Intent-to-Treat Population (ITT) consisted of all randomized patients whether or not randomized treatment was administered.</population>
      <group_list>
        <group group_id="B1">
          <title>Dabrafenib and Trametinib Combination Therapy</title>
          <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
        </group>
        <group group_id="B2">
          <title>Dabrafenib and Trametinib Placebos</title>
          <description>Subjects received matching placebos orally for 12 months</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="438"/>
            <count group_id="B2" value="432"/>
            <count group_id="B3" value="870"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50.4" spread="14.17"/>
                    <measurement group_id="B2" value="50.5" spread="13.14"/>
                    <measurement group_id="B3" value="50.4" spread="13.66"/>
                  </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="195"/>
                    <measurement group_id="B2" value="193"/>
                    <measurement group_id="B3" value="388"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="243"/>
                    <measurement group_id="B2" value="239"/>
                    <measurement group_id="B3" value="482"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="432"/>
                    <measurement group_id="B2" value="427"/>
                    <measurement group_id="B3" value="859"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Relapse-free Survival (RFS)</title>
        <description>Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.</description>
        <time_frame>Approximately 3.5 years</time_frame>
        <population>Intent-to-Treat (ITT) Population</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib Combination Therapy</title>
            <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
          </group>
          <group group_id="O2">
            <title>Dabrafenib and Trametinib Placebos</title>
            <description>Subjects received matching placebos orally for 12 months</description>
          </group>
        </group_list>
        <measure>
          <title>Relapse-free Survival (RFS)</title>
          <description>Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.</description>
          <population>Intent-to-Treat (ITT) Population</population>
          <units>Participants with events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="438"/>
                <count group_id="O2" value="432"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Relapsed (event)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="163"/>
                    <measurement group_id="O2" value="247"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Died</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Censored, follow-up ended</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43"/>
                    <measurement group_id="O2" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Censored, follow-up ongoing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="229"/>
                    <measurement group_id="O2" value="149"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, where λ is the hazard ratio (HR) of combination therapy relative to placebo.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Hazard ratio is obtained from the stratified Pike estimator. A hazard ratio &lt;1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.</non_inferiority_desc>
            <p_value>&lt; 0.0001</p_value>
            <method>Log Rank</method>
            <param_type>Hazard Ratio, log</param_type>
            <param_value>0.47</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>0.58</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo</description>
        <time_frame>approximately 3.5 years</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib Combination Therapy</title>
            <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
          </group>
          <group group_id="O2">
            <title>Dabrafenib and Trametinib Placebos</title>
            <description>Subjects received matching placebos orally for 12 months</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo</description>
          <population>ITT population</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="438"/>
                <count group_id="O2" value="432"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Died (event)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60"/>
                    <measurement group_id="O2" value="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Censored, follow-up ended</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47"/>
                    <measurement group_id="O2" value="62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Censored, follow-up ongoing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="331"/>
                    <measurement group_id="O2" value="277"/>
                  </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>Hazard ratio is obtained from the stratified Pike estimator.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A hazard ratio &lt;1 indicates a lower risk with dabrafenib + trametinib compared with Placebo.</non_inferiority_desc>
            <p_value>0.006</p_value>
            <method>Log Rank</method>
            <method_desc>the two-sided threshold for significance at this first interim analysis was p=0.000019</method_desc>
            <param_type>Hazard Ratio, log</param_type>
            <param_value>0.57</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>0.79</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Distant Metastasis-free Survival</title>
        <description>Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.</description>
        <time_frame>approximately 3.5 years</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib Combination Therapy</title>
            <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
          </group>
          <group group_id="O2">
            <title>Dabrafenib and Trametinib Placebos</title>
            <description>Subjects received matching placebos orally for 12 months</description>
          </group>
        </group_list>
        <measure>
          <title>Distant Metastasis-free Survival</title>
          <description>Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.</description>
          <population>ITT population</population>
          <units>Participants with events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="438"/>
                <count group_id="O2" value="432"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Number of Subjects - Relapsed</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="106"/>
                    <measurement group_id="O2" value="150"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Subjects - died</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Subjects - censored, follow-up ended</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="99"/>
                    <measurement group_id="O2" value="131"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Subjects - follow-up ongoing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="229"/>
                    <measurement group_id="O2" value="149"/>
                  </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>Hazard ratio is estimated using Pike estimator.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A hazard ratio &lt;1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.</non_inferiority_desc>
            <param_type>Hazard Ratio, log</param_type>
            <param_value>0.51</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.40</ci_lower_limit>
            <ci_upper_limit>0.65</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Freedom From Relapse</title>
        <description>Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.</description>
        <time_frame>approximately 3.5 years</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib Combination Therapy</title>
            <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
          </group>
          <group group_id="O2">
            <title>Dabrafenib and Trametinib Placebos</title>
            <description>Subjects received matching placebos orally for 12 months</description>
          </group>
        </group_list>
        <measure>
          <title>Freedom From Relapse</title>
          <description>Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.</description>
          <population>ITT population</population>
          <units>Participants with events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="438"/>
                <count group_id="O2" value="432"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Number of Subjects - relapsed</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="163"/>
                    <measurement group_id="O2" value="247"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Subjects - died</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Subjects - censored, follow-up ended</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44"/>
                    <measurement group_id="O2" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Subjects - censored, follow-up ongoing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="229"/>
                    <measurement group_id="O2" value="149"/>
                  </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>Hazard ratio is estimated using Pike estimator.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A hazard ratio &lt;1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.</non_inferiority_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.47</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>0.57</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events (AEs) were collected from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious AEs (SAEs) were reported over the same time period as AEs except SAEs assessed as related to study participation, study treatment or concomitant medication were recorded from the time a subject consents to participate in the study up to and including any follow-up contact.</time_frame>
      <desc>All cause mortality provided for the treatment period only.</desc>
      <group_list>
        <group group_id="E1">
          <title>Dabrafenib + Trametinib Combination Therapy</title>
          <description>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.</description>
        </group>
        <group group_id="E2">
          <title>Dabrafenib and Trametinib Placebos</title>
          <description>Subjects received matching placebos orally for 12 months</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (19.1)</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="4" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="155" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="44" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Haemorrhagic anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pancytopenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Atrioventricular block second degree</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Cardiac ventricular thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Inappropriate antidiuretic hormone secretion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Chorioretinopathy</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Iritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Macular oedema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Retinal detachment</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Uveitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Visual acuity reduced</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Inguinal hernia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pancreatic toxicity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Proctalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Retroperitoneal haematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="67" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Systemic inflammatory response syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Drug-induced liver injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hepatic haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hepatotoxicity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hyperbilirubinaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abscess jaw</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Cholecystitis infective</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Epstein-Barr virus infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Erysipelas</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Febrile infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Groin abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Groin infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Parvovirus infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Post procedural infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Rash pustular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Retinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Salpingitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Soft tissue infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Subcutaneous abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Vulval abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Limb injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Post procedural haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Seroma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Upper limb fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Right ventricular systolic pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Transaminases increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Troponin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Diabetes mellitus inadequate control</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Intervertebral disc protrusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Myopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Rhabdomyolysis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </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" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>B-cell lymphoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Bladder transitional cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Bowen's disease</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Colon adenoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Endometrial adenocarcinoma</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Focal nodular hyperplasia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Keratoacanthoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Lentigo maligna</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Malignant melanoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Malignant melanoma in situ</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Prostate cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Renal cancer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Salivary gland adenoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma of skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Amyotrophic lateral sclerosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Carpal tunnel syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Demyelinating polyneuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Facial paralysis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Loss of consciousness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Meningoradiculitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Peripheral sensorimotor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Obsessive-compulsive disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Calculus urinary</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Nephrotic syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Renal colic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Ovarian disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Priapism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Testicular mass</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Lung disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pulmonary hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Erythema nodosum</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Panniculitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Rash generalised</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Lymphoedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Vascular occlusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (19.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="414" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="340" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="27" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="51" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="143" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="65" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="172" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="88" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="120" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="43" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="58" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="42" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="158" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="204" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="122" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="66" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="58" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="248" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="44" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Folliculitis</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="48" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="64" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="61" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="47" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="25" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="119" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="61" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="38" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="34" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="39" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="70" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="40" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="60" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="38" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="169" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="102" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="73" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="39" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" subjects_affected="54" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="55" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="32" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="48" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Night sweats</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysaesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="40" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="106" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="47" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="432"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="49" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="35" subjects_at_risk="432"/>
              </event>
              <event>
                <sub_title>Lymphoedema</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="435"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="432"/>
              </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 terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis Pharmaceuticals</organization>
      <phone>862-778-8300</phone>
      <email>Novartis.email@novartis.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01682083
org study id: 115532
secondary id: 2012-001266-15
secondary id: CDRB436F2301
nct id: NCT01682083
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination
      with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical
      resection. Patients with completely resected, histologically confirmed, BRAF V600E/K
      mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc]
      cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either
      dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD])
      combination therapy or two placebos for 12 months.
This was a two-arm, randomized, double-blind, multi-center, international phase III study of
      dabrafenib in combination with trametinib versus two matching placebos in the adjuvant
      treatment of melanoma after surgical resection. Patients with completely resected,
      histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node
      metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. Subjects
      were randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and
      trametinib (2 mg once daily [QD]). None of the patients had undergone previous systemic
      anticancer treatment or radiotherapy for melanoma. All the patients had undergone completion
      lymphadenectomy with no clinical or radiographic evidence of residual regional node disease
      within 12 weeks before randomization, had recovered from definitive surgery, and had an
      Eastern Cooperative Oncology Group performance status of 0 or 1. BRAF V600 mutation status
      was confirmed in primary-tumor or lymph-node tissue by a central reference laboratory. All
      the patients provided written informed consent.

      The primary end point was recurrence-free survival, Overall survival, as the key secondary
      end point, was to be tested in a hierarchical manner only if the primary end point met the
      criteria for significance. The overall survival analysis used a preplanned three-look
      Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary, which was used to
      determine the significance threshold for the first interim overall survival analysis
      (two-sided P=0.000019).

      Disease assessments included clinical examination and imaging by means of computed
      tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months during
      the first 24 months, then every 6 months until disease recurrence or the completion of the
      trial. Follow-up for survival began after recurrence and continued through the end of the
      trial. Adverse events and laboratory values were assessed at screening, on the date of
      randomization, at least once per month through month 12, and at every visit for
      disease-recurrence assessment after month 12. Adverse events and laboratory values were
      graded according to the Common Terminology Criteria for Adverse Events, version 4.0.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Relapse-free Survival (RFS)
time frame: Approximately 3.5 years
description: Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.
measure: Overall Survival
time frame: approximately 3.5 years
description: Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo
measure: Distant Metastasis-free Survival
time frame: approximately 3.5 years
description: Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.
measure: Freedom From Relapse
time frame: approximately 3.5 years
description: Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.
arm group label: Dabrafenib and trametinib
arm group type: Experimental
description: Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
arm group label: Dabrafenib and trametinib placebos
arm group type: Placebo Comparator
description: Subjects received matching placebos orally for 12 months
intervention type: Drug
intervention name: Dabrafenib
description: Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)
arm group label: Dabrafenib and trametinib
other name: GSK2118436
intervention type: Drug
intervention name: Trametinib
description: Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)
arm group label: Dabrafenib and trametinib
other name: GSK1120212
intervention type: Drug
intervention name: Placebos
description: The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment
arm group label: Dabrafenib and trametinib placebos
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: Argentina
country: Australia
country: Austria
country: Belgium
country: Brazil
country: Canada
country: Czechia
country: Denmark
country: France
country: Germany
country: Greece
country: Israel
country: Italy
country: Japan
country: Netherlands
country: New Zealand
country: Norway
country: Poland
country: Russian Federation
country: Spain
country: Sweden
country: Switzerland
country: Taiwan
country: United Kingdom
country: United States
country: Czech Republic
country: Finland
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Trametinib
mesh term: Dabrafenib
sharing ipd: Yes
ipd description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 