<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/NCT01708174</url>
  </required_header>
  <id_info>
    <org_study_id>CLDE225C2301</org_study_id>
    <nct_id>NCT01708174</nct_id>
  </id_info>
  <brief_title>A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)</brief_title>
  <official_title>A Phase II, Multi-center, Open-label, Single-arm Study of the Efficacy and Safety of Oral LDE225 in Patients With Hh-pathway Activated Relapsed Medulloblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This Phase II study evaluated the safety and efficacy of LDE225 in adult and pediatric&#xD;
      patients with Hh-pathway activated, relapsed MB.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study was a single-arm study of the efficacy and safety of oral sonidegib in patients&#xD;
      with Hh-pathway activated relapsed medulloblastoma. It was initially designed as a&#xD;
      randomized, controlled, open-label phase III study of adults and children with Hh-pathway&#xD;
      activated MB whose disease had failed standard of care therapy, including radiation therapy&#xD;
      (RT). The original study consisted of a randomized controlled part and a non-randomized&#xD;
      uncontrolled part. Approximately 69 patients were to be randomized in a 2:1 ratio to receive&#xD;
      sonidegib oral suspension or the active control, temozolomide (TMZ) capsules. Randomization&#xD;
      was to be stratified according to age, &lt;18 years versus ≥ 18 years. Approximately 40 patients&#xD;
      were to receive sonidegib in the non-randomized uncontrolled part of the study. Following the&#xD;
      enrollment of 11 patients, the study was amended to become a phase II single-arm study with&#xD;
      only sonidegib, and the target enrollment was changed to 20 patients. Prior to the study&#xD;
      amendment, TMZ participants whose disease progressed while on TMZ were permitted to crossover&#xD;
      to sonidegib. After the amendment, participants receiving TMZ were crossed over to sonidegib.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 6, 2013</start_date>
  <completion_date type="Actual">October 5, 2016</completion_date>
  <primary_completion_date type="Actual">October 5, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants With Overall Response Rate (ORR) According to Independent Review Committee (IRC) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</measure>
    <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
    <description>ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). Assessments after crossover were not included for TMZ participants.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) According to IRC From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</measure>
    <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
    <description>PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). TMZ participants without event prior to crossover were censored.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</measure>
    <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
    <description>PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause. PFS was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With ORR According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</measure>
    <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
    <description>ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). ORR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. Assessments after crossover were not included for TMZ patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</measure>
    <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
    <description>DoR was defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma. DoR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. TMZ participants without an event prior to crossover were censored.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</measure>
    <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
    <description>OS was defined as the time from date of randomization to date of death due to any cause. All deaths are considered, including deaths occurred after crossover for TMZ participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)</measure>
    <time_frame>Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53</time_frame>
    <description>Blood samples were collected for assessment. The children's group was analyzed up until week 25 only.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Medulloblastoma</condition>
  <arm_group>
    <arm_group_label>Sonidegib (LDE225)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>600 mg orally for adults and 500 mg/m2 orally for children</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Temozolamide (TMZ)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LDE225</intervention_name>
    <description>Sonidegib for oral suspension was supplied in amber glass bottles. Sonidegib oral suspension was combined with the supplied reconstitution vehicle to a final concentration of 50 mg/mL.</description>
    <arm_group_label>Sonidegib (LDE225)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TMZ</intervention_name>
    <description>Temozolomide capsules were obtained locally by the Investigator</description>
    <arm_group_label>Temozolamide (TMZ)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with histologically confirmed diagnosis of MB, who have experienced relapse&#xD;
             or progression after standard-of-care therapy including radiotherapy. Patients&#xD;
             currently receiving steroids must have been on a stable (or decreasing) dose for at&#xD;
             least 5 days before initiating study therapy.&#xD;
&#xD;
          -  Only patients with a test result, using the 5-gene Hh signature assay, indicating&#xD;
             Hhpathway activated MB are eligible for this study. All available tumor material&#xD;
             obtained at any time during the course of the patient's disease should be submitted&#xD;
             for these analyses&#xD;
&#xD;
          -  At least one measurable lesion defined as lesion(s) that can be accurately measured in&#xD;
             at least two dimensions and is ≥ 10 mm in each dimension by Gadolinium (Gd)-MRI,&#xD;
             irrespective of slice thickness/reconstruction interval, for CNS lesions and CT or MRI&#xD;
             (with or without contrast) for non-CNS lesions. All patients with CNS lesions must&#xD;
             have a brain MRI with and without gadolinium and a spine MRI with gadolinium within 2&#xD;
             weeks prior to first dose of study treatment.&#xD;
&#xD;
          -  Performance Status corresponding to ECOG score of 0, 1, or 2:&#xD;
&#xD;
               1. Karnofsky performance status score ≥ 50 for patients &gt;16 years of age&#xD;
&#xD;
               2. Lansky performance status score ≥ 50 for patients ≤ 16 years of age&#xD;
&#xD;
          -  Adequate bone marrow function as defined as:&#xD;
&#xD;
               1. Peripheral absolute neutrophil count (ANC) ≥ 1.5 x 109/L&#xD;
&#xD;
               2. Platelet count ≥ 80 x 109/L&#xD;
&#xD;
               3. Hemoglobin (Hgb) ≥ 9 g/dL&#xD;
&#xD;
          -  Serum CK ≤1.5 ULN&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior treatment with a Smoothened inhibitor Systemic anticancer treatment within 2&#xD;
             weeks before first dose of study treatment (6 weeks for nitrosourea, mitomycin, and&#xD;
             monoclonal antibodies).&#xD;
&#xD;
          -  Focal radiation therapy within 4 weeks before first dose of study treatment, or full&#xD;
             spinal radiotherapy within 3 months before first dose of study treatment.&#xD;
&#xD;
          -  Patients who have neuromuscular disorders that are associated with elevated CK (eg,&#xD;
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal&#xD;
             muscular atrophy).&#xD;
&#xD;
          -  Patients receiving treatment with medications that are known to be strong inhibitors&#xD;
             or inducers of CYP3A4/5 or are metabolized by CYP2B6 and CYP2C9, that have narrow&#xD;
             therapeutic indices that cannot be discontinued at least 2 weeks before first dose of&#xD;
             study treatment and for the duration of the study&#xD;
&#xD;
          -  Patients receiving unstable or increasing doses of corticosteroids. If patients are on&#xD;
             corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose must&#xD;
             have been stabilized (or decreasing) for at least 5 days before first dose of study&#xD;
             treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Months</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>Ann &amp; Robert H. Lurie Children Dept of Oncology</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Dept Onc</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute SC-7</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center- New York Presbyterian Dept of Oncology</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center Division of Hema/Onco.</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229-3039</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Pittsburgh Dept of Oncology</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213-2583</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas/MD Anderson Cancer Center SC-3</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030-4009</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Cancer Care Alliance Dept Oncology</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Herston</city>
        <state>Queensland</state>
        <zip>4029</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Perth</city>
        <state>Western Australia</state>
        <zip>6840</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sao Paulo</city>
        <state>SP</state>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1Z6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bordeaux</city>
        <state>Aquitaine</state>
        <zip>33076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Angers Cedex 1</city>
        <zip>49033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lille Cedex</city>
        <zip>59020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Paris</city>
        <zip>75231</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>Vandoeuvre les Nancy</city>
        <zip>54511</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>Augsburg</city>
        <zip>86156</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bologna</city>
        <state>BO</state>
        <zip>40139</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Roma</city>
        <state>RM</state>
        <zip>00165</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Torino</city>
        <state>TO</state>
        <zip>101126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Torino</city>
        <state>TO</state>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rotterdam</city>
        <zip>3015 CN</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rotterdam</city>
        <zip>3075 EA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Moskow</city>
        <state>Russia</state>
        <zip>117198</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sevilla</city>
        <state>Andalucia</state>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <state>Catalunya</state>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Esplugues de Llobregat</city>
        <state>Catalunya</state>
        <zip>08950</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Valencia</city>
        <state>Comunidad Valenciana</state>
        <zip>46026</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28009</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>Goteborg</city>
        <zip>413 45</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Zürich</city>
        <zip>8032</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sutton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</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>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Brazil</country>
    <country>Canada</country>
    <country>France</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Belgium</country>
    <country>Hungary</country>
    <country>Israel</country>
    <country>Poland</country>
  </removed_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>October 11, 2012</study_first_submitted>
  <study_first_submitted_qc>October 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 16, 2012</study_first_posted>
  <results_first_submitted>March 31, 2017</results_first_submitted>
  <results_first_submitted_qc>May 16, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">June 14, 2017</results_first_posted>
  <last_update_submitted>August 7, 2017</last_update_submitted>
  <last_update_submitted_qc>August 7, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>medulloblastoma,</keyword>
  <keyword>relapsed,</keyword>
  <keyword>pediatric,</keyword>
  <keyword>children,</keyword>
  <keyword>adults,</keyword>
  <keyword>Hh pathway inhibitor,</keyword>
  <keyword>LDE225</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Medulloblastoma</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Analyses were performed by treatment and by age group.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Sonidegib (LDE225) Children</title>
          <description>500 mg/m2 orally</description>
        </group>
        <group group_id="P2">
          <title>Sonidegib (LDE225) Adults</title>
          <description>600 mg orally</description>
        </group>
        <group group_id="P3">
          <title>Temozolomide (TMZ)</title>
          <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Treatment Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="16"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Pharmacokinetic Analysis Set</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="13"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Progressive disease</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Survival Follow-up</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Sonidegib (LDE225) Children</title>
          <description>500 mg/m2 orally</description>
        </group>
        <group group_id="B2">
          <title>Sonidegib (LDE225) Adults</title>
          <description>600 mg orally</description>
        </group>
        <group group_id="B3">
          <title>Temozolomide (TMZ)</title>
          <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
        </group>
        <group group_id="B4">
          <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="2"/>
            <count group_id="B2" value="16"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8.5" spread="6.36" lower_limit="4.0" upper_limit="13.0"/>
                    <measurement group_id="B2" value="37.0" spread="8.17" lower_limit="24.0" upper_limit="51.0"/>
                    <measurement group_id="B3" value="35.5" spread="3.16" lower_limit="31.0" upper_limit="38.0"/>
                    <measurement group_id="B4" value="35.0" spread="10.73" lower_limit="4.0" upper_limit="51.0"/>
                  </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="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Overall Response Rate (ORR) According to Independent Review Committee (IRC) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
        <description>ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). Assessments after crossover were not included for TMZ participants.</description>
        <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
        <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
          <group group_id="O3">
            <title>Temozolomide (TMZ)</title>
            <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Overall Response Rate (ORR) According to Independent Review Committee (IRC) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
          <description>ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). Assessments after crossover were not included for TMZ participants.</description>
          <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0"/>
                    <measurement group_id="O2" value="18.8"/>
                    <measurement group_id="O3" value="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) According to IRC From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
        <description>PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). TMZ participants without event prior to crossover were censored.</description>
        <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
        <population>The FAS was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
          <group group_id="O3">
            <title>Temozolomide (TMZ)</title>
            <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) According to IRC From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
          <description>PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). TMZ participants without event prior to crossover were censored.</description>
          <population>The FAS was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6" lower_limit="NA" upper_limit="NA">The lower and upper 95% confidence intervals (CI) were not estimable because there were only 2 participants analyzed. With only 2 participants, it is not uncommon to have 'not estimable' for the limits.</measurement>
                    <measurement group_id="O2" value="3.3" lower_limit="1.7" upper_limit="17.1"/>
                    <measurement group_id="O3" value="2.9" lower_limit="0.9" upper_limit="4.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PFS According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
        <description>PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause. PFS was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma.</description>
        <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
        <population>The FAS was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
          <group group_id="O3">
            <title>Temozolomide (TMZ)</title>
            <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
          </group>
        </group_list>
        <measure>
          <title>PFS According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
          <description>PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause. PFS was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma.</description>
          <population>The FAS was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="1.6" upper_limit="NA">The median and upper limit of the 95% confidence interval were not estimable because there were too few events.</measurement>
                    <measurement group_id="O2" value="3.3" lower_limit="1.6" upper_limit="13.0"/>
                    <measurement group_id="O3" value="2.9" lower_limit="0.9" upper_limit="4.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With ORR According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
        <description>ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). ORR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. Assessments after crossover were not included for TMZ patients.</description>
        <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
        <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
          <group group_id="O3">
            <title>Temozolomide (TMZ)</title>
            <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With ORR According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
          <description>ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). ORR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. Assessments after crossover were not included for TMZ patients.</description>
          <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0"/>
                    <measurement group_id="O2" value="25.0"/>
                    <measurement group_id="O3" value="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response (DoR) According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
        <description>DoR was defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma. DoR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. TMZ participants without an event prior to crossover were censored.</description>
        <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
        <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
          <group group_id="O3">
            <title>Temozolomide (TMZ)</title>
            <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response (DoR) According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
          <description>DoR was defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma. DoR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. TMZ participants without an event prior to crossover were censored.</description>
          <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">The median and lower and upper 95% CI could not be calculated because there were too few events.</measurement>
                    <measurement group_id="O2" value="8.5" lower_limit="4.1" upper_limit="16.6"/>
                    <measurement group_id="O3" value="NA" lower_limit="NA" upper_limit="NA">The median and lower and upper 95% CI could not be calculated because there were too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
        <description>OS was defined as the time from date of randomization to date of death due to any cause. All deaths are considered, including deaths occurred after crossover for TMZ participants.</description>
        <time_frame>from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016</time_frame>
        <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
          <group group_id="O3">
            <title>Temozolomide (TMZ)</title>
            <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016</title>
          <description>OS was defined as the time from date of randomization to date of death due to any cause. All deaths are considered, including deaths occurred after crossover for TMZ participants.</description>
          <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="4.5" upper_limit="NA">The median and upper 95% CI could not be calculated because there were too few events.</measurement>
                    <measurement group_id="O2" value="9.5" lower_limit="4.9" upper_limit="15.6"/>
                    <measurement group_id="O3" value="NA" lower_limit="1.2" upper_limit="NA">The median and upper 95% CI could not be calculated because there were too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)</title>
        <description>Blood samples were collected for assessment. The children's group was analyzed up until week 25 only.</description>
        <time_frame>Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53</time_frame>
        <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Sonidegib (LDE225) Children</title>
            <description>500 mg/m2 orally</description>
          </group>
          <group group_id="O2">
            <title>Sonidegib (LDE225) Adults</title>
            <description>600 mg orally</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)</title>
          <description>Blood samples were collected for assessment. The children's group was analyzed up until week 25 only.</description>
          <population>The full analysis set (FAS) was analyzed. The FAS included all randomized and non-randomized participants who received at least one dose of study treatment.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 1 (n=2,11)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.00" spread="0.00"/>
                    <measurement group_id="O2" value="0.00" spread="0.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 3 (n=2,10)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2890" spread="1240"/>
                    <measurement group_id="O2" value="761" spread="519"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 5 (n=2,8)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4930" spread="1380"/>
                    <measurement group_id="O2" value="1090" spread="700"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 7 (n=1,8)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2810" spread="NA">Standard deviation (SD) does not apply when n=1.</measurement>
                    <measurement group_id="O2" value="1450" spread="842"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 9 (n=1,8)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4670" spread="NA">SD does not apply when n=1.</measurement>
                    <measurement group_id="O2" value="1530" spread="682"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 13 (n=1,4)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3680" spread="NA">SD does not apply when n=1.</measurement>
                    <measurement group_id="O2" value="2330" spread="1100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 17 (n=1,6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3060" spread="NA">SD does not apply when n=1.</measurement>
                    <measurement group_id="O2" value="1880" spread="730"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 21 (n=1,5)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3770" spread="NA">SD does not apply when n=1.</measurement>
                    <measurement group_id="O2" value="2270" spread="915"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 25 (n=1,4)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1890" spread="NA">SD does not apply when n=1.</measurement>
                    <measurement group_id="O2" value="2050" spread="625"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 29 (n=NA,4)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2050" spread="906"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 33 (n=NA,4)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2180" spread="512"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 37 (n=NA,3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2850" spread="306"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 41 (n=NA,4)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2370" spread="916"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 45 (n=NA,2)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2890" spread="290"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 49 (n=NA,2)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2330" spread="990"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 53 (n=NA,2)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">PK analysis for the Children group was done up until week 25 only.</measurement>
                    <measurement group_id="O2" value="2080" spread="764"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Sonidegib (LDE225) Children</title>
          <description>500 mg/m2 orally</description>
        </group>
        <group group_id="E2">
          <title>Sonidegib (LDE225) Adults</title>
          <description>600 mg orally</description>
        </group>
        <group group_id="E3">
          <title>Sonidegib (Total)</title>
          <description>Sonidegib (Total)</description>
        </group>
        <group group_id="E4">
          <title>Temozolomide (TMZ)</title>
          <description>150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (19.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>NAUSEA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>VOMITING</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>GENERAL PHYSICAL HEALTH DETERIORATION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>BACTERIAL SEPSIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>CLOSTRIDIAL INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>LUNG INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>SEPSIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ASPARTATE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BLOOD CREATINE PHOSPHOKINASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>DEHYDRATION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPERNATRAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPONATRAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>BACK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>NECK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>SEIZURE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Product Issues</title>
            <event_list>
              <event>
                <sub_title>THROMBOSIS IN DEVICE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>CONFUSIONAL STATE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DRUG DEPENDENCE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HALLUCINATION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </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="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DYSPNOEA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </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="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (19.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>ANAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>THROMBOCYTOPENIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>ATRIOVENTRICULAR BLOCK FIRST DEGREE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>SINUS TACHYCARDIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>EAR CONGESTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>VERTIGO</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>DIABETES INSIPIDUS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>DIPLOPIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PHOTOPHOBIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>VISION BLURRED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>ABDOMINAL DISTENSION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ABDOMINAL PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ABDOMINAL PAIN UPPER</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>AEROPHAGIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ANAL INCONTINENCE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>CONSTIPATION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DIARRHOEA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DYSPHAGIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HAEMATOCHEZIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>NAUSEA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PARAESTHESIA ORAL</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>REGURGITATION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>TOOTH DISCOLOURATION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>TOOTH LOSS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>VOMITING</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>ASTHENIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>FATIGUE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>GAIT DISTURBANCE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>NON-CARDIAC CHEST PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>OEDEMA PERIPHERAL</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PYREXIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>ALLERGY TO ARTHROPOD BITE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>ACINETOBACTER INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>FOLLICULITIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ORAL HERPES</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>RHINITIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>UPPER RESPIRATORY TRACT INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>URINARY TRACT INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ALANINE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ASPARTATE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BLOOD ALKALINE PHOSPHATASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BLOOD CREATINE PHOSPHOKINASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BLOOD CREATINE PHOSPHOKINASE MB INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BLOOD CREATININE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BLOOD PHOSPHORUS INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BODY TEMPERATURE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>C-REACTIVE PROTEIN INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>CRYSTAL URINE PRESENT</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>GRANULOCYTE COUNT INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>LYMPHOCYTE COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>OXYGEN SATURATION DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PLATELET COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PROTHROMBIN TIME PROLONGED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>RED BLOOD CELL COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>RED BLOOD CELL SEDIMENTATION RATE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>WEIGHT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>WHITE BLOOD CELL COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </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="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>FAILURE TO THRIVE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPERCALCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPERGLYCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPERURICAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPOALBUMINAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPOCALCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPOKALAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPOMAGNESAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPONATRAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPOPHOSPHATAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </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="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>BACK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>MUSCLE SPASMS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>MYALGIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>NECK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PAIN IN EXTREMITY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>APHASIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ATAXIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>CEREBROSPINAL FLUID LEAKAGE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DEPRESSED LEVEL OF CONSCIOUSNESS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DIZZINESS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DROOLING</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DYSARTHRIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DYSGEUSIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>FACIAL NERVE DISORDER</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HEADACHE</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HEMIPARESIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>IIIRD NERVE DISORDER</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>LETHARGY</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>MUSCLE SPASTICITY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>MYOCLONUS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>NEUROPATHY PERIPHERAL</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>NYSTAGMUS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PARAESTHESIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PERIPHERAL MOTOR NEUROPATHY</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PYRAMIDAL TRACT SYNDROME</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>SCIATICA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>SOMNOLENCE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>SYNCOPE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>CONFUSIONAL STATE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DELIRIUM</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DEPRESSION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>INSOMNIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>IRRITABILITY</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>HAEMATURIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>MICTURITION URGENCY</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PROTEINURIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>URINARY RETENTION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>APNOEA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ATELECTASIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>COUGH</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DYSPNOEA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>EPISTAXIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PNEUMONITIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PRODUCTIVE COUGH</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </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="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DERMATITIS ACNEIFORM</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>DRY SKIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>ERYTHEMA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPERHIDROSIS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>PRURITUS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>RASH</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>RASH MACULO-PAPULAR</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>HAEMATOMA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPERTENSION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>HYPOTENSION</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>THROMBOSIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
              </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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis Pharmaceuticals</organization>
      <phone>862-778-8300</phone>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01708174
org study id: CLDE225C2301
nct id: NCT01708174
lead sponsor: 
has dmc: No
This Phase II study evaluated the safety and efficacy of LDE225 in adult and pediatric
      patients with Hh-pathway activated, relapsed MB.
This study was a single-arm study of the efficacy and safety of oral sonidegib in patients
      with Hh-pathway activated relapsed medulloblastoma. It was initially designed as a
      randomized, controlled, open-label phase III study of adults and children with Hh-pathway
      activated MB whose disease had failed standard of care therapy, including radiation therapy
      (RT). The original study consisted of a randomized controlled part and a non-randomized
      uncontrolled part. Approximately 69 patients were to be randomized in a 2:1 ratio to receive
      sonidegib oral suspension or the active control, temozolomide (TMZ) capsules. Randomization
      was to be stratified according to age, <18 years versus ≥ 18 years. Approximately 40 patients
      were to receive sonidegib in the non-randomized uncontrolled part of the study. Following the
      enrollment of 11 patients, the study was amended to become a phase II single-arm study with
      only sonidegib, and the target enrollment was changed to 20 patients. Prior to the study
      amendment, TMZ participants whose disease progressed while on TMZ were permitted to crossover
      to sonidegib. After the amendment, participants receiving TMZ were crossed over to sonidegib.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Participants With Overall Response Rate (ORR) According to Independent Review Committee (IRC) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
time frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
description: ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). Assessments after crossover were not included for TMZ participants.
measure: Progression Free Survival (PFS) According to IRC From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
time frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
description: PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). TMZ participants without event prior to crossover were censored.
measure: PFS According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
time frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
description: PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause. PFS was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma.
measure: Percentage of Participants With ORR According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
time frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
description: ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). ORR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. Assessments after crossover were not included for TMZ patients.
measure: Duration of Response (DoR) According to Local Investigator Assessment From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
time frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
description: DoR was defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma. DoR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. TMZ participants without an event prior to crossover were censored.
measure: Overall Survival (OS) From Date First Participant Randomized, 13-Sep-2013 to Date of Data Cut-off, 15-Nov-2016
time frame: from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
description: OS was defined as the time from date of randomization to date of death due to any cause. All deaths are considered, including deaths occurred after crossover for TMZ participants.
measure: Pharmacokinetics (PK): Summary of Plasma Trough Concentrations for Sonidegib (LDE225)
time frame: Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53
description: Blood samples were collected for assessment. The children's group was analyzed up until week 25 only.
arm group label: Sonidegib (LDE225)
arm group type: Experimental
description: 600 mg orally for adults and 500 mg/m2 orally for children
arm group label: Temozolamide (TMZ)
arm group type: Active Comparator
description: 150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.
intervention type: Drug
intervention name: LDE225
description: Sonidegib for oral suspension was supplied in amber glass bottles. Sonidegib oral suspension was combined with the supplied reconstitution vehicle to a final concentration of 50 mg/mL.
arm group label: Sonidegib (LDE225)
intervention type: Drug
intervention name: TMZ
description: Temozolomide capsules were obtained locally by the Investigator
arm group label: Temozolamide (TMZ)
criteria: 
gender: All
minimum age: 4 Months
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: Australia
country: Brazil
country: Canada
country: France
country: Germany
country: Italy
country: Netherlands
country: Russian Federation
country: Spain
country: Sweden
country: Switzerland
country: United Kingdom
country: United States
country: Belgium
country: Hungary
country: Israel
country: Poland
responsible party type: Sponsor
mesh term: Medulloblastoma
participant flow: 
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reported events: 
certain agreements: 
point of contact: 