<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/NCT03277690</url>
  </required_header>
  <id_info>
    <org_study_id>COR-2017-01</org_study_id>
    <nct_id>NCT03277690</nct_id>
  </id_info>
  <brief_title>A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome.</brief_title>
  <official_title>A Double-blind, Placebo-Controlled, Randomized Withdrawal Following Open Label Therapy Study to Assess the Safety and Efficacy of Levoketoconazole (2S, 4R-ketoconazole) in the Treatment of Endogenous Cushing's Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cortendo AB</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cortendo AB</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration&#xD;
      study in subjects with endogenous Cushing's Syndrome (CS) previously treated with single-arm,&#xD;
      open-label levoketoconazole that will assess efficacy, safety, tolerability, and&#xD;
      pharmacokinetics of levoketoconazole.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration&#xD;
      study in subjects with endogenous CS that will assess efficacy, safety, tolerability, and&#xD;
      Pharmacokinetics (PK) of levoketoconazole. There are two populations (cohorts) of subjects:&#xD;
      (1) subjects which were previous levoketoconazole study completers and (2) subjects that are&#xD;
      levoketoconazole treatment naïve subjects.&#xD;
&#xD;
      Study methodology varies by cohort prior to randomization only. Following initial screening&#xD;
      (washout as needed) and Dose Titration and Maintenance Periods, as applicable, this study&#xD;
      will be conducted in two double-blind phases (a Withdrawal Phase and a Restoration Phase).&#xD;
      The levoketoconazole-naïve cohort will need to go through the Dose Titration and Maintenance&#xD;
      Phase. The longest anticipated total study participation duration is approximately 51 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 26, 2017</start_date>
  <completion_date type="Actual">August 31, 2020</completion_date>
  <primary_completion_date type="Actual">June 30, 2020</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Subjects With Loss of Therapeutic Response to Levoketoconazole Upon Withdrawing to Placebo Compared With the Proportion of Subjects With Loss of Therapeutic Response Upon Continuing Treatment With Levoketoconazole.</measure>
    <time_frame>max. 9.5 weeks</time_frame>
    <description>Urinary free cortisol (UFC) level measurement: Loss of therapeutic response is inferred based on mUFC from three 24-hour UFC measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is above the ULN (i.e. &gt;1.0X ULN)1, OR (3) an early rescue criterion is met.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">84</enrollment>
  <condition>Endogenous Cushing's Syndrome</condition>
  <arm_group>
    <arm_group_label>Levoketoconazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levoketoconazole</intervention_name>
    <description>During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.&#xD;
During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.</description>
    <arm_group_label>Levoketoconazole</arm_group_label>
    <other_name>COR-003</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>During the double-blind Withdrawal Phase, patients will receive placebo tablets.&#xD;
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
        SONICS STUDY COMPLETERS:&#xD;
&#xD;
        Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical&#xD;
        response on a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to&#xD;
        study entry.&#xD;
&#xD;
        ALL OTHERS:&#xD;
&#xD;
          -  Confirmed newly diagnosed, persistent or recurrent endogenous Cushing's syndrome of&#xD;
             any etiology, except secondary to malignancy (including pituitary or adrenal&#xD;
             carcinoma).&#xD;
&#xD;
          -  Elevated mean 24-hour Urinary Free Cortisol (UFC) levels at least 1.5X upper limit of&#xD;
             the normative range of the study's central laboratory assay and from a minimum of&#xD;
             three measurements from adequately collected urine.&#xD;
&#xD;
          -  Presence of abnormal values from at least one of these two diagnostic tests:&#xD;
&#xD;
               -  Abnormal Dexamethasone Suppression Test (DST) OR&#xD;
&#xD;
               -  Elevated late night salivary cortisol concentrations (at least two measurements)&#xD;
                  each greater than the upper limit of the study's central laboratory normative&#xD;
                  range&#xD;
&#xD;
          -  Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed&#xD;
             until after study completion and agree to complete this study prior to surgery.&#xD;
&#xD;
          -  If post-surgical for CS-specific surgery, then no significant post-operative sequelae&#xD;
             remain and the risk of such sequelae is considered negligible.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
        Subjects will be excluded from the study if ANY of the following criteria are met (NOTE:&#xD;
        exclusion criteria apply to and must be assessed in both cohorts):&#xD;
&#xD;
          -  Enrolled in SONICS but have not completed SONICS through Visit M12.&#xD;
&#xD;
          -  Pseudo-Cushing's syndrome based on assessment of the Investigator.&#xD;
&#xD;
          -  Cyclic Cushing's syndrome with multi-week periods of apparent spontaneous CS&#xD;
             remission.&#xD;
&#xD;
          -  Non-endogenous source of hypercortisolism, including pharmacological corticosteroids&#xD;
             or ACTH.&#xD;
&#xD;
          -  Radiotherapy of any modality directed against the source of hypercortisolism within&#xD;
             the last 5 years.&#xD;
&#xD;
          -  Treatment with mitotane within 6 months of enrollment.&#xD;
&#xD;
          -  History of malignancy, including adrenal or pituitary carcinomas (other than low-risk,&#xD;
             well-differentiated carcinomas of thyroid, breast or prostate that are very unlikely&#xD;
             to require further treatment in the opinion of the treating physician, or squamous&#xD;
             cell or basal cell carcinoma of the skin).&#xD;
&#xD;
          -  Clinical or radiological signs of compression of the optic chiasm.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xavier Valencia, MD</last_name>
    <role>Study Director</role>
    <affiliation>Cortendo AB</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Keck Medical Center University of Southern California HCII, Internal Medicine - Keck Hospital</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center, Cedars-Sinai Pituitary Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCLA School of Medicine, Medicine/Endocrinology Department</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Center for Diabetes and Endocrine Care</name>
      <address>
        <city>Fort Lauderdale</city>
        <state>Florida</state>
        <zip>33312</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University, Neurosurgery</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University, Medicine - Endocrinology</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University, Endocrinology Department</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan, Comprehensive Endocrine Research, Internal Medicine - MEND</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine, Endocrinology</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University, College of P&amp;S Medicine/Neuro-endocrine Unit</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center, Endocrinology</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University, Neurological Surgery</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allegheny Neuroendocrinology Center, West Penn Allegheny Health System</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alexandovska University Hospital, Clinic of Endocrinology &amp; Metabolic Diseases</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Multiprofile Hospital for Active Treatment &quot;Aleksandrovska&quot; EAD Clinic of Endocrinology and Metabolic Diseases</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Specialized Hospital for Active Treatment in Endocrinology (USHATE) I Klinika</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet, Copenhagen University Hospital, Endocrinology Department</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>APHM Hôpital de la Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques</name>
      <address>
        <city>Marseille</city>
        <state>Cedex 5</state>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Evangelismos Athens General Hospital, Department of Endocrinology</name>
      <address>
        <city>Athens</city>
        <zip>10676</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>General Hospital of Athens 'G. Gennimatas', Department of Endocrinology-Diabetes Centre</name>
      <address>
        <city>Athens</city>
        <zip>11527</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>General Hospital of Athens 'Laiko', &quot;National and Kapodistrian University of Athens Medical School Pathophysiology - Endocrinology&quot;</name>
      <address>
        <city>Athens</city>
        <zip>11527</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University General Hospital of Ioannina, Department of Endocrinology</name>
      <address>
        <city>Ioánnina</city>
        <zip>45110</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hippokration General Hospital, &quot;Endocrinology and Diabetes Department</name>
      <address>
        <city>Thessaloníki</city>
        <zip>54642</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Semmelweis Egyetem II. Belgyógyászati Klinika A.épület I.emelet ODM-labor</name>
      <address>
        <city>Budapest</city>
        <zip>1088</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bnai Zion Medical Center, Institute of Endocrinology</name>
      <address>
        <city>Haifa</city>
        <zip>34802</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rabin Medical Center- Beilinson Hospital, &quot;Institute of Endocrinology &amp; Metabolism, Beilinson Campus&quot;</name>
      <address>
        <city>Petach Tikva</city>
        <zip>49100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tel-Aviv Sourasky Medical Center Institute of Endocrinology, Metabolism and Hypertension</name>
      <address>
        <city>Tel Aviv</city>
        <zip>642-3906</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica di Endocrinologia e malattie del Metabolismo, Dipartimento Specialità Mediche</name>
      <address>
        <city>Ancona</city>
        <zip>60126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Genova, Department of Internal Medicine &amp; Medical Specialties (DiMI)</name>
      <address>
        <city>Genova</city>
        <zip>16132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Policlinico G. Martino Sezione di Endocrinologia</name>
      <address>
        <city>Messina</city>
        <zip>98125</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Federico II, Sezione di Endocrinologia (Edificio 1, Secondo Piano)</name>
      <address>
        <city>Napoli</city>
        <zip>8031</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Endocrinology</name>
      <address>
        <city>Roma</city>
        <zip>00168</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico Universitario Sant'Andrea, Scienze Mediche</name>
      <address>
        <city>Roma</city>
        <zip>00189</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Citta della Salure e della Scienza SC Endocrinologia, Diabetologia e Metabolismo</name>
      <address>
        <city>Torino</city>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leiden University, Leiden University Medical Center, Department of Endocrinology</name>
      <address>
        <city>Leiden</city>
        <zip>2333ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus Medical Center, Department of Internal Medicine</name>
      <address>
        <city>Rotterdam</city>
        <zip>3015CE</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maria Sklodowska-Curie Memorial Institute - Cancer Center Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department</name>
      <address>
        <city>Gliwice</city>
        <zip>44-101</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wojskowy Instytut Medyczny, Klinika Gastroenterologii, Endokrynologii I Chorob Wewnetrznych</name>
      <address>
        <city>Warsaw</city>
        <zip>04-141</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instytut Centrum Zdrowia Matki Polki, Oddział Endokrynologii i Chorób Metabolicznych</name>
      <address>
        <city>Łódź</city>
        <zip>93-338</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spitalul Clinic Judetean Mures, Compartimentul de Endocrinologie</name>
      <address>
        <city>Târgu-Mureş</city>
        <state>Mures</state>
        <zip>540072</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spitalul Clinic Judetean de Urgenta &quot;Pius Brinzeu&quot;, Departamentul de Endocrinologie</name>
      <address>
        <city>Timişoara</city>
        <state>Timis</state>
        <zip>300723</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institutul National de Endocrinologie C.I. Parhon, Sectia Clinica de Endocrinologie II, Patologia tiroidei de corelatie</name>
      <address>
        <city>Bucuresti</city>
        <zip>011863</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Sectia Clinica Endocrinologie</name>
      <address>
        <city>Cluj-Napoca</city>
        <zip>400349</zip>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universidad De La Ribera, Endocrinologia</name>
      <address>
        <city>Alzira</city>
        <state>Valencia</state>
        <zip>46600</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramón y Cajal, Endocrinology and Nutrition</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bulgaria</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Romania</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>September 7, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <results_first_submitted>April 15, 2022</results_first_submitted>
  <results_first_submitted_qc>October 13, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">November 8, 2022</results_first_posted>
  <disposition_first_submitted>March 12, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>October 13, 2022</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">November 8, 2022</disposition_first_posted>
  <last_update_submitted>October 13, 2022</last_update_submitted>
  <last_update_submitted_qc>October 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cushing Syndrome, Adrenocortical Hyperfunction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cushing Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 23, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT03277690/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 13, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT03277690/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Variable therapeutic response results in customized therapeutic doses (TD). The study design included an initial Titration-maintenance phase to identify a TD for each subject. It included a requirement for maintenance at TD for at least 4 weeks prior to entering the Randomized-withdrawal (RW) phase. Then a 1:1 RW to placebo was used to establish efficacy of the active therapy. 5 additional subjects began directly in RW after completing the parent study without requiring re-titration to TD.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Levoketoconazole</title>
          <description>Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo&#xD;
Levoketoconazole: During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.&#xD;
During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole&#xD;
Placebo: During the double-blind Withdrawal Phase, patients will receive placebo tablets.&#xD;
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Dose Titration and Maintenance</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="79"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor decision - Randomization closed</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Randomized Withdrawal</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Subjects Which Were Previous Levoketoconazole Study Completers</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Subjects That Are Levoketoconazole Treatment naïve Subjects</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </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_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Restoration</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Subjects Which Were Previous Levoketoconazole Study Completers</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Subjects That Are Levoketoconazole Treatment naïve Subjects</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Levoketoconazole</title>
          <description>Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo&#xD;
Levoketoconazole: During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.&#xD;
During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole&#xD;
Placebo: During the double-blind Withdrawal Phase, patients will receive placebo tablets.&#xD;
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="22"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="44"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="45.0" spread="11.97"/>
                    <measurement group_id="B2" value="43.6" spread="10.96"/>
                    <measurement group_id="B3" value="44.3" spread="11.36"/>
                  </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="15"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Greece</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Romania</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hungary</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Poland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Italy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Israel</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bulgaria</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>France</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Spain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Receiving Anti-hypertensive Medication at Baseline</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Receiving Anti-diabetic Medication at Baseline</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Anatomical etiology of endogenous Cushing's syndrome</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Cushing's Disease</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="38"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Ectopic ACTH Secretion</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Adrenal-Dependent</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Mean Urinary Free Cortisol (mUFC)</title>
          <units>nmol/24 hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="738.69" spread="1067.025"/>
                    <measurement group_id="B2" value="411.59" spread="436.176"/>
                    <measurement group_id="B3" value="575.14" spread="822.384"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects With Loss of Therapeutic Response to Levoketoconazole Upon Withdrawing to Placebo Compared With the Proportion of Subjects With Loss of Therapeutic Response Upon Continuing Treatment With Levoketoconazole.</title>
        <description>Urinary free cortisol (UFC) level measurement: Loss of therapeutic response is inferred based on mUFC from three 24-hour UFC measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is above the ULN (i.e. &gt;1.0X ULN)1, OR (3) an early rescue criterion is met.</description>
        <time_frame>max. 9.5 weeks</time_frame>
        <population>Intent to Treat (ITT)</population>
        <group_list>
          <group group_id="O1">
            <title>Levoketoconazole</title>
            <description>Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo&#xD;
Levoketoconazole: During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.&#xD;
During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole&#xD;
Placebo: During the double-blind Withdrawal Phase, patients will receive placebo tablets.&#xD;
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With Loss of Therapeutic Response to Levoketoconazole Upon Withdrawing to Placebo Compared With the Proportion of Subjects With Loss of Therapeutic Response Upon Continuing Treatment With Levoketoconazole.</title>
          <description>Urinary free cortisol (UFC) level measurement: Loss of therapeutic response is inferred based on mUFC from three 24-hour UFC measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is above the ULN (i.e. &gt;1.0X ULN)1, OR (3) an early rescue criterion is met.</description>
          <population>Intent to Treat (ITT)</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The intent to treat (ITT) population adverse events (AEs) are reported for the length of time the subject was in the randomized withdrawal (RW) phase, up to 9.5 weeks. The safety population AEs are reported for the full study length from informed consent to end of study, up to approximately 51 weeks.</time_frame>
      <desc>Untoward medical occurrence in a study subject that is temporally associated with the use of a medicinal product, regardless of its potential relationship to the medicinal product. An AE, therefore, can be any unfavorable or unintended sign, including an abnormal laboratory finding, symptom, or disease (new or exacerbated), whether related to the study drug or study conduct or not. NOTE: Abnormal values that reflect hypercortisolism (UFCs, LNSC and serum cortisol) will not be recorded as AEs.</desc>
      <group_list>
        <group group_id="E1">
          <title>Levoketoconazole-ITT RW Phase</title>
          <description>During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.</description>
        </group>
        <group group_id="E2">
          <title>Placebo- ITT RW Phase</title>
          <description>During the double-blind Withdrawal Phase, patients will receive placebo tablets.</description>
        </group>
        <group group_id="E3">
          <title>Safety Population</title>
          <description>The safety population for the study overall (i.e., all phases combined), referred to all subjects who received at least 1 dose of study drug during any of the 3 study phases. This includes the subjects in the TM phase as well as the additional subjects who began directly in RW who completed the parent study and did not require re-titration to a therapeutic dose.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Pancreatitis chronic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Umbilical hernia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Liver disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Drug-induced liver injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Limb Injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Nephropathy toxic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-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="11" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="73" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Tachycardia paroxysmal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Ventricular extrasystoles</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Adrenal insufficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="24" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Lip Dry</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Thirst</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Tonsillitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Wrist fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood glucose increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Blood insulin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Cortisol free urine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT prolonged</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Hypercholesterolaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="21" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Increased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Nocturia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Ovarian cyst</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Polymenorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchitis chronic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Acne</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="84"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="84"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="84"/>
              </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 only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Xeris Medical Director</name_or_title>
      <organization>Cortendo AB</organization>
      <phone>+1 610-254-9200</phone>
      <email>LOGICS@cortendo.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03277690
org study id: COR-2017-01
nct id: NCT03277690
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration
      study in subjects with endogenous Cushing's Syndrome (CS) previously treated with single-arm,
      open-label levoketoconazole that will assess efficacy, safety, tolerability, and
      pharmacokinetics of levoketoconazole.
This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration
      study in subjects with endogenous CS that will assess efficacy, safety, tolerability, and
      Pharmacokinetics (PK) of levoketoconazole. There are two populations (cohorts) of subjects:
      (1) subjects which were previous levoketoconazole study completers and (2) subjects that are
      levoketoconazole treatment naïve subjects.

      Study methodology varies by cohort prior to randomization only. Following initial screening
      (washout as needed) and Dose Titration and Maintenance Periods, as applicable, this study
      will be conducted in two double-blind phases (a Withdrawal Phase and a Restoration Phase).
      The levoketoconazole-naïve cohort will need to go through the Dose Titration and Maintenance
      Phase. The longest anticipated total study participation duration is approximately 51 weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Subjects With Loss of Therapeutic Response to Levoketoconazole Upon Withdrawing to Placebo Compared With the Proportion of Subjects With Loss of Therapeutic Response Upon Continuing Treatment With Levoketoconazole.
time frame: max. 9.5 weeks
description: Urinary free cortisol (UFC) level measurement: Loss of therapeutic response is inferred based on mUFC from three 24-hour UFC measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is above the ULN (i.e. >1.0X ULN)1, OR (3) an early rescue criterion is met.
arm group label: Levoketoconazole
arm group type: Experimental
description: Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo
arm group label: Placebo
arm group type: Placebo Comparator
description: Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole
intervention type: Drug
intervention name: Levoketoconazole
description: During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.
During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.
arm group label: Levoketoconazole
other name: COR-003
intervention type: Drug
intervention name: Placebo
description: During the double-blind Withdrawal Phase, patients will receive placebo tablets.
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Xavier Valencia, MD
role: Study Director
affiliation: Cortendo AB
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country: Bulgaria
country: Denmark
country: France
country: Greece
country: Hungary
country: Israel
country: Italy
country: Netherlands
country: Poland
country: Romania
country: Spain
country: United States
responsible party type: Sponsor
mesh term: Cushing Syndrome
mesh term: Syndrome
sharing ipd: No
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