<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/NCT03760666</url>
  </required_header>
  <id_info>
    <org_study_id>CCB-01</org_study_id>
    <nct_id>NCT03760666</nct_id>
  </id_info>
  <brief_title>A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia</brief_title>
  <official_title>A Phase 1b/2a Open-label, Multi-center Study to Assess the Safety, Efficacy and Pharmacokinetics of Intrapatient Dose-adjusted Brequinar and Inhibition of Dihydroorotate Dehydrogenase (DHODH) in Adult Subjects With AML</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Clear Creek Bio, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Clear Creek Bio, Inc.</source>
  <oversight_info>
    <has_dmc>No</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>
      A Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety,&#xD;
      tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid&#xD;
      leukemia (AML). Ribavirin BID may be added to brequinar twice weekly in eligible subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Up to 27 subjects will be entered in this Phase 1b/2a multi-center, open-label,&#xD;
      non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted&#xD;
      brequinar in adult subjects with acute myeloid leukemia (AML). Active Cohort 2 subjects on&#xD;
      brequinar alone twice weekly may roll over into brequinar twice weekly + ribavirin BID.&#xD;
      Cohort 3 subjects will begin treatment with brequinar alone twice weekly then move to&#xD;
      brequinar twice weekly + ribavirin BID as tolerated. Both the brequinar and ribavirin doses&#xD;
      may be adjusted based on safety, tolerability, and enzyme inhibition levels.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    No efficacy observed, COVID-19 caused sites to shut down&#xD;
  </why_stopped>
  <start_date type="Actual">December 20, 2018</start_date>
  <completion_date type="Actual">February 9, 2021</completion_date>
  <primary_completion_date type="Actual">December 31, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Subjects start dosing with brequinar alone; Cohort 2 subjects may roll over into ribavirin dosing; Cohort 3 subjects started with brequinar monotherapy then added ribavirin dosing.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Treatment-Related Adverse Events</measure>
    <time_frame>12 months</time_frame>
    <description>The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>12 months</time_frame>
    <description>The number of participants in the Efficacy Analysis Set with best overall response of one of the responses of CR, CRi, CRh, PR, of MLFS. No participant met the efficacy endpoint to be included in this analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Remission (CR) Rate</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>The proportion of subjects in the Efficacy Analysis Set with best overall response of CR. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Remission With Incomplete Hematologic Recovery (CRi) Rate</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Remission With Partial Hematological Recovery (CRh) Rate</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Morphologic Leukemia Free State (MLFS) Rate</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Partial Remission (PR) Rate</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event Free Survival (EFS) Rate</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>Interval between first dose and relapse (&gt;=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>The duration of response is defined as the number of days from the time response criteria are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. No participant met this efficacy endpoint to be included in this analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brequinar Pharmacokinetics - Area Under the Curve (AUC)</measure>
    <time_frame>First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.</time_frame>
    <description>The plot of drug concentration in blood plasma vs. time.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Brequinar/Brequinar + Ribavirin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Brequinar and ribavirin were dosed orally; brequinar starting doses ranged from 200 mg/m2 to 500 mg/m2. Brequinar doses were adjusted by cohort for starting dose and regimen (either twice-weekly or once-weekly). In addition, the dose for each participant was also adjusted (either escalated or decreased) based on safety, brequinar PK and levels of dihydroorotate (DHO). Ribavirin 1000 mg twice a day (bid) was added in combination with brequinar for the final 3 study participants.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Brequinar/Brequinar + Ribavirin</intervention_name>
    <description>The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.</description>
    <arm_group_label>Brequinar/Brequinar + Ribavirin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 1. Willing and able to provide written informed consent for the trial.&#xD;
&#xD;
          2. Patients 18 years of age or older, with relapsed/refractory AML by World Health&#xD;
             Organization classification, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or&#xD;
             mixed phenotypic acute leukemia (MPAL) and who have exhausted available therapy.&#xD;
&#xD;
          3. ECOG Performance Status 0 to 2.&#xD;
&#xD;
          4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA&#xD;
             Class 0 to 2.&#xD;
&#xD;
          5. Adequate hepatic function (unless deemed to be related to underlying leukemia).&#xD;
&#xD;
               1. Direct bilirubin ≤ 2 x ULN&#xD;
&#xD;
               2. ALT ≤ 3 x ULN&#xD;
&#xD;
               3. AST ≤ 3 x ULN&#xD;
&#xD;
          6. Adequate renal function as documented by creatinine clearance ≥ 50 mL/min based on the&#xD;
             Cockcroft-Gault equation.&#xD;
&#xD;
          7. In the absence of rapidly proliferative disease, the interval from prior&#xD;
             leukemia-directed therapy to first dose of study drug will be at least 7 days for&#xD;
             cytotoxic or non-cytotoxic (immunotherapy) agents. Use of supportive care measures per&#xD;
             institution's standard of care is permitted at any time.&#xD;
&#xD;
          8. The effects of brequinar on the developing human fetus are unknown. For this reason,&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for&#xD;
             the duration of study participation. Should a woman become pregnant or suspect she is&#xD;
             pregnant while she or her partner is participating in this study, she should inform&#xD;
             her treating physician immediately. Men treated or enrolled on this protocol must also&#xD;
             agree to use adequate contraception prior to the study, for the duration of study&#xD;
             participation, and for 90 days after completion of brequinar administration.&#xD;
&#xD;
          9. Male subjects must agree to refrain from sperm donation from initial study drug&#xD;
             administration until 90 days after the last dose of study drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients in need of immediate leukapheresis.&#xD;
&#xD;
          2. Any concurrent uncontrolled clinically significant medical condition, laboratory&#xD;
             abnormality, or psychiatric illness that could place the participant at unacceptable&#xD;
             risk of study treatment.&#xD;
&#xD;
          3. QTc interval using Fridericia's formula (QTcF) ≥ 470 msec. Participants with a bundle&#xD;
             branch block and prolonged QTc interval may be eligible after discussion with the&#xD;
             medical monitor.&#xD;
&#xD;
          4. Pre-existing liver disease.&#xD;
&#xD;
          5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted&#xD;
             during study with the following exceptions:&#xD;
&#xD;
             a. Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS&#xD;
             leukemia.&#xD;
&#xD;
          6. Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥&#xD;
             0.5 mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g.&#xD;
             cyclosporine or other calcineurin inhibitors or other immunosuppressive agents used&#xD;
             for GVHD).&#xD;
&#xD;
          7. Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia&#xD;
             (BLL), or mixed phenotypic acute leukemia (MPAL).&#xD;
&#xD;
          8. Diagnosis of acute promyelocytic leukemia (APL)&#xD;
&#xD;
          9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.&#xD;
&#xD;
         10. Severe gastrointestinal or metabolic condition that could interfere with the&#xD;
             absorption of oral study medication.&#xD;
&#xD;
         11. Prior malignancy, unless it has not been active or has remained stable for at least 2&#xD;
             years. Participants with treated non-melanoma skin cancer, in situ carcinoma or&#xD;
             cervical intraepithelial neoplasia, regardless of the disease-free duration, are&#xD;
             eligible if definitive treatment for the condition has been completed. Participants&#xD;
             with organ-confined prostate cancer with no evidence of recurrent or progressive&#xD;
             disease are eligible if at the active surveillance stage, hormonal therapy has been&#xD;
             initiated, or the malignancy has been surgically removed or treated with definitive&#xD;
             radiotherapy.&#xD;
&#xD;
         12. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy&#xD;
             test.&#xD;
&#xD;
         13. Documented hemoglobinopathy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>City of Hope</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beth-Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic Lerner College of Medicine</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>November 27, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <results_first_submitted>March 2, 2022</results_first_submitted>
  <results_first_submitted_qc>August 5, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">August 8, 2022</results_first_posted>
  <last_update_submitted>August 5, 2022</last_update_submitted>
  <last_update_submitted_qc>August 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>DHODH</keyword>
  <keyword>Brequinar</keyword>
  <keyword>Differentiation</keyword>
  <keyword>IMPDH Inhibition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ribavirin</mesh_term>
    <mesh_term>Brequinar</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Clear Creek Bio is committed to responsible data sharing regarding the clinical trials we sponsor. Data that may be shared include access to anonymized participant and trial level data (analysis data sets), as well as other information (e.g., protocol) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Requests for data can be submitted at any time and if the below conditions are met data will be accessible for 12 months, with possible extensions considered.</ipd_time_frame>
    <ipd_access_criteria>Requests for data may be made by qualified researchers who plan to engage in rigorous, independent scientific research. Data will be provided following review and approval of a research proposal including a formal statistical analysis plan and execution of a Data Sharing Agreement.</ipd_access_criteria>
  </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>March 9, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/66/NCT03760666/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>September 11, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/66/NCT03760666/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Cohort 1 (N = 5) 12/20/2018 - 04/01/2019. Cohort 2 (N = 11) 10/25/2019 - 11/20/2020. Cohort 3 (N = 1) 01/12/21 - 02/03/2021. Participants were enrolled at hematology oncology units at major hospitals. Only 17 of the 27 planned participants were enrolled due to lack of efficacy with either brequinar monotherapy or the brequinar + ribavirin combination. Participants were to be treated in the study for up to one year.</recruitment_details>
      <pre_assignment_details>All subjects had relapsed/refractory AML and had no other viable treatment options. Data were reported and analyzed by cohort.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1</title>
          <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2</title>
          <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
        </group>
        <group group_id="P3">
          <title>Cohort 3</title>
          <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="11"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="11"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>AML Disease Progression</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Data were reported and analyzed by cohort.</population>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1</title>
          <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2</title>
          <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
        </group>
        <group group_id="B3">
          <title>Cohort 3</title>
          <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="5"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="1"/>
            <count group_id="B4" value="17"/>
          </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="60.4" spread="20.89"/>
                    <measurement group_id="B2" value="72.5" spread="7.13"/>
                    <measurement group_id="B3" value="66.0" spread="0"/>
                    <measurement group_id="B4" value="68.8" spread="13.15"/>
                  </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="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="14"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="4"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="11"/>
                  </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 group_id="B4" 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="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </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>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Surface Area</title>
          <units>meters squared</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.94" spread="0.126"/>
                    <measurement group_id="B2" value="1.82" spread="0.306"/>
                    <measurement group_id="B3" value="2.0" spread="0"/>
                    <measurement group_id="B4" value="1.86" spread="0.259"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG (European Cooperative Oncology Group</title>
          <description>The ECOG Scale of Performance Status describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working). The range is 0 to 5; A score of 0 indicates fully active without restrictions, a score of 5 is Dead.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>ECOG Score of 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECOG Score of 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECOG Score of 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Treatment-Related Adverse Events</title>
        <description>The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.</description>
        <time_frame>12 months</time_frame>
        <population>The Safety Population was used for this analysis. The Safety Population consisted of all subjects who were enrolled in the study and received at least one dose of brequinar. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>The 5 subjects in Cohort 1 started dosing with brequinar monotherapy at 500 mg/m2 on a twice-weekly basis.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>A total of 11 subjects were enrolled into Cohort 2. Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-Related Adverse Events</title>
          <description>The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.</description>
          <population>The Safety Population was used for this analysis. The Safety Population consisted of all subjects who were enrolled in the study and received at least one dose of brequinar. Data were reported and analyzed by cohort.</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="5"/>
                <count group_id="O2" value="11"/>
                <count group_id="O3" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate (ORR)</title>
        <description>The number of participants in the Efficacy Analysis Set with best overall response of one of the responses of CR, CRi, CRh, PR, of MLFS. No participant met the efficacy endpoint to be included in this analysis</description>
        <time_frame>12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR)</title>
          <description>The number of participants in the Efficacy Analysis Set with best overall response of one of the responses of CR, CRi, CRh, PR, of MLFS. No participant met the efficacy endpoint to be included in this analysis</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Complete Remission (CR) Rate</title>
        <description>The proportion of subjects in the Efficacy Analysis Set with best overall response of CR. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Remission (CR) Rate</title>
          <description>The proportion of subjects in the Efficacy Analysis Set with best overall response of CR. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Complete Remission With Incomplete Hematologic Recovery (CRi) Rate</title>
        <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Remission With Incomplete Hematologic Recovery (CRi) Rate</title>
          <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Complete Remission With Partial Hematological Recovery (CRh) Rate</title>
        <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>All subjects started dosing with brequinar monotherapy at 500 mg/m2 on a twice-weekly basis.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Remission With Partial Hematological Recovery (CRh) Rate</title>
          <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Morphologic Leukemia Free State (MLFS) Rate</title>
        <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Morphologic Leukemia Free State (MLFS) Rate</title>
          <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Partial Remission (PR) Rate</title>
        <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Partial Remission (PR) Rate</title>
          <description>The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Event Free Survival (EFS) Rate</title>
        <description>Interval between first dose and relapse (&gt;=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Event Free Survival (EFS) Rate</title>
          <description>Interval between first dose and relapse (&gt;=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response</title>
        <description>The duration of response is defined as the number of days from the time response criteria are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. No participant met this efficacy endpoint to be included in this analysis.</description>
        <time_frame>Up to approximately 12 months</time_frame>
        <population>Subjects with a response. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response</title>
          <description>The duration of response is defined as the number of days from the time response criteria are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. No participant met this efficacy endpoint to be included in this analysis.</description>
          <population>Subjects with a response. No subjects achieved this status. Data were reported and analyzed by cohort.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brequinar Pharmacokinetics - Area Under the Curve (AUC)</title>
        <description>The plot of drug concentration in blood plasma vs. time.</description>
        <time_frame>First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.</time_frame>
        <population>This population included subjects who completed at least Week 1 of the study. Results are based on Week 1 samples obtained on the first day of dosing at baseline (pre-dose) then at Hour 1, 2, 4, and 6. Data were reported and analyzed by cohort.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>All subjects started dosing with brequinar monotherapy at 500 mg/m2 on a twice-weekly basis.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
          </group>
        </group_list>
        <measure>
          <title>Brequinar Pharmacokinetics - Area Under the Curve (AUC)</title>
          <description>The plot of drug concentration in blood plasma vs. time.</description>
          <population>This population included subjects who completed at least Week 1 of the study. Results are based on Week 1 samples obtained on the first day of dosing at baseline (pre-dose) then at Hour 1, 2, 4, and 6. Data were reported and analyzed by cohort.</population>
          <units>micrograms.hr/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="11"/>
                <count group_id="O3" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="501.0" spread="354.5"/>
                    <measurement group_id="O2" value="546.5" spread="564.1"/>
                    <measurement group_id="O3" value="130.5" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>up to 1 year</time_frame>
      <desc>An adverse event is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.&#xD;
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing will be entered on the AE form. Subjects will be questioned and observed for evidence of AEs, whether or not related to study drug.&#xD;
Data were reported and analyzed by cohort.</desc>
      <group_list>
        <group group_id="E1">
          <title>Cohort 1</title>
          <description>5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly.</description>
        </group>
        <group group_id="E2">
          <title>Cohort 2</title>
          <description>Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis.</description>
        </group>
        <group group_id="E3">
          <title>Cohort 3</title>
          <description>One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 21.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Mucosal inflammation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacteremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetes mellitus inadequate control</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Leukemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Intracranial hematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 21.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>anemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Febrile Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Epigastric discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hemorrhoidal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Large intestine perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lip blister</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Tongue erythema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Mucosal inflammation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Edema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Clostridium difficile colitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Corona virus infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pneumonia fungal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Animal scratch</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Incision site rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Limb injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Post-traumatic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Procedural pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin laceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin wound</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Transfusion reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Upper limb fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Urine output decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Fluid retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Malnutrition</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Hemangioma of skin</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Migraine with aura</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Micturition urgency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pollakiuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nasal dryness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pleuritic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pulmonary mass</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Rhinitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Decubitus ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Petechia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Rash maculopapular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin exfoliation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Swelling face</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>CCB-01 was a small, open-label study in patients who had exhausted all other therapy options for their relapsed/refractory acute myeloid leukemia (AML). The study was stopped early due to lack of efficacy and inability to recruit new patients during the COVID-19 pandemic.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Vice President, Clinical Operations</name_or_title>
      <organization>Clear Creek Bio, Inc.</organization>
      <phone>(617) 765-2252</phone>
      <email>clinical@clearcreekbio.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/NCT03760666
org study id: CCB-01
nct id: NCT03760666
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
A Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety,
      tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid
      leukemia (AML). Ribavirin BID may be added to brequinar twice weekly in eligible subjects.
Up to 27 subjects will be entered in this Phase 1b/2a multi-center, open-label,
      non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted
      brequinar in adult subjects with acute myeloid leukemia (AML). Active Cohort 2 subjects on
      brequinar alone twice weekly may roll over into brequinar twice weekly + ribavirin BID.
      Cohort 3 subjects will begin treatment with brequinar alone twice weekly then move to
      brequinar twice weekly + ribavirin BID as tolerated. Both the brequinar and ribavirin doses
      may be adjusted based on safety, tolerability, and enzyme inhibition levels.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: Subjects start dosing with brequinar alone; Cohort 2 subjects may roll over into ribavirin dosing; Cohort 3 subjects started with brequinar monotherapy then added ribavirin dosing.
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Treatment-Related Adverse Events
time frame: 12 months
description: The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.
measure: Overall Response Rate (ORR)
time frame: 12 months
description: The number of participants in the Efficacy Analysis Set with best overall response of one of the responses of CR, CRi, CRh, PR, of MLFS. No participant met the efficacy endpoint to be included in this analysis
measure: Complete Remission (CR) Rate
time frame: Up to approximately 12 months
description: The proportion of subjects in the Efficacy Analysis Set with best overall response of CR. No participant met this efficacy endpoint to be included in this analysis.
measure: Complete Remission With Incomplete Hematologic Recovery (CRi) Rate
time frame: Up to approximately 12 months
description: The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi. No participant met this efficacy endpoint to be included in this analysis.
measure: Complete Remission With Partial Hematological Recovery (CRh) Rate
time frame: Up to approximately 12 months
description: The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh. No participant met this efficacy endpoint to be included in this analysis.
measure: Morphologic Leukemia Free State (MLFS) Rate
time frame: Up to approximately 12 months
description: The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS. No participant met this efficacy endpoint to be included in this analysis.
measure: Partial Remission (PR) Rate
time frame: Up to approximately 12 months
description: The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR. No participant met this efficacy endpoint to be included in this analysis.
measure: Event Free Survival (EFS) Rate
time frame: Up to approximately 12 months
description: Interval between first dose and relapse (>=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both. No participant met this efficacy endpoint to be included in this analysis.
measure: Duration of Response
time frame: Up to approximately 12 months
description: The duration of response is defined as the number of days from the time response criteria are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. No participant met this efficacy endpoint to be included in this analysis.
measure: Brequinar Pharmacokinetics - Area Under the Curve (AUC)
time frame: First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.
description: The plot of drug concentration in blood plasma vs. time.
arm group label: Brequinar/Brequinar + Ribavirin
arm group type: Experimental
description: Brequinar and ribavirin were dosed orally; brequinar starting doses ranged from 200 mg/m2 to 500 mg/m2. Brequinar doses were adjusted by cohort for starting dose and regimen (either twice-weekly or once-weekly). In addition, the dose for each participant was also adjusted (either escalated or decreased) based on safety, brequinar PK and levels of dihydroorotate (DHO). Ribavirin 1000 mg twice a day (bid) was added in combination with brequinar for the final 3 study participants.
intervention type: Drug
intervention name: Brequinar/Brequinar + Ribavirin
description: The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.
arm group label: Brequinar/Brequinar + Ribavirin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Ribavirin
mesh term: Brequinar
sharing ipd: Yes
ipd description: Clear Creek Bio is committed to responsible data sharing regarding the clinical trials we sponsor. Data that may be shared include access to anonymized participant and trial level data (analysis data sets), as well as other information (e.g., protocol) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: Requests for data can be submitted at any time and if the below conditions are met data will be accessible for 12 months, with possible extensions considered.
ipd access criteria: Requests for data may be made by qualified researchers who plan to engage in rigorous, independent scientific research. Data will be provided following review and approval of a research proposal including a formal statistical analysis plan and execution of a Data Sharing Agreement.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: CCB-01 was a small, open-label study in patients who had exhausted all other therapy options for their relapsed/refractory acute myeloid leukemia (AML). The study was stopped early due to lack of efficacy and inability to recruit new patients during the COVID-19 pandemic.
point of contact: 