<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/NCT02968134</url>
  </required_header>
  <id_info>
    <org_study_id>HREC/16/QRBW/377</org_study_id>
    <nct_id>NCT02968134</nct_id>
  </id_info>
  <brief_title>Single Dose Population Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients</brief_title>
  <acronym>POSA</acronym>
  <official_title>Single Dose Population Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal Brisbane and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The University of Queensland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Royal Brisbane and Women's Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to try to find out how critically ill patients receiving the&#xD;
      anti fungal medication, posaconazole, process it in their body. Investigators would like to&#xD;
      study if the recommended doses of posaconazole achieve adequate concentrations in the&#xD;
      patients blood to treat fungal infections.The disease process in critically ill patients can&#xD;
      profoundly influence the concentration of anti fungal medication in the blood. The process by&#xD;
      which a drug travels through the body in blood, how it is broken down and removed by the body&#xD;
      is called pharmacokinetics (PK).&#xD;
&#xD;
      This information is important to know because if antifungal levels are low in the blood, the&#xD;
      fungal infection has an opportunity to become resistant to the antifungal medication which&#xD;
      can lead to the medication being less effective against the fungal infection potentially&#xD;
      exposing future patients with infection to a limited range of effective antifungals.&#xD;
&#xD;
      Investigators can measure the PK by taking blood samples at specific times after the anti&#xD;
      fungal medication is given.&#xD;
&#xD;
      This study will enroll 8 patients who are admitted to the intensive care unit and are being&#xD;
      treated with an antifungal medication for a fungal infection. Patients will be consented and&#xD;
      given a single dose of posaconazole and serial blood samples will be collected just prior to&#xD;
      the dose and at 15, 45,75 minutes during the infusion and at 3, 5, 8, 12, 18, 24, 30 36 and&#xD;
      48 hours . Information about the patients stay in the ICU will also be collected including&#xD;
      blood pressure, temperature, blood test results.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Posaconazole is a new extended spectrum triazole active against a range of yeasts and molds&#xD;
      including Aspergillus, Candida, Coccidioides, Cryptococcus neoformans, Fusarium, and&#xD;
      Zygomycetes. It may be used for the prevention of invasive fungal infections in&#xD;
      immunocompromised patients including febrile neutropenic patients and those receiving&#xD;
      immunosuppressant drugs for graft-vs-host disease during stem cell transplantation. It may&#xD;
      also be used for treatment of systemic fungal infections.The use of posaconazole in ICU&#xD;
      patients has been limited to stable patients to ensure reliable bioavailability from the oral&#xD;
      formulations. Oral formulations have important limitation in that they cannot be used in&#xD;
      critically ill patients who may be unable to take oral doses or bioavailability may be&#xD;
      compromised due to erratic absorption. Recently, an intravenous (IV) formulation has been&#xD;
      developed to address these limitations. Initial pharmacokinetic (PK) investigations of the IV&#xD;
      formulation were conducted in hematology patients, with further data in other patient&#xD;
      populations still forthcoming; particularly in the critically ill where the IV formulation&#xD;
      would probably be used most frequently.&#xD;
&#xD;
      Most of the available PK data for posaconazole is from non-critically ill patients who&#xD;
      received the oral formulation. Although the absorption phase of the kinetics is not relevant&#xD;
      for the IV formulation, data on the distribution, metabolism and elimination properties would&#xD;
      still be informative of the IV kinetics. The tissue distribution of posaconazole is extensive&#xD;
      with a very large volume of distribution owing to its high lipophilicity. It is highly bound&#xD;
      to plasma proteins (98-99%) and therefore very likely to be affected by the variable changes&#xD;
      in plasma protein concentration in critically ill patients. The major elimination pathway of&#xD;
      posaconazoleis through biliary excretion (about 77%) of mainly the unchanged parent compound&#xD;
      and the rest through renal execration of as a glucuronide conjugate.&#xD;
&#xD;
      A number of studies have described PK variability of posaconazole due to altered&#xD;
      absorption/bioavailability which can frequently result in sub-therapeutic plasma&#xD;
      concentrations, forming strong case for therapeutic drug monitoring. Nonetheless, it is&#xD;
      unclear whether the observed low concentrations can also be explained, at least in part, by&#xD;
      other factors such as disease-related PK changes or if the obvious plausibility of altered&#xD;
      absorption has masked such investigations. Most population PK models described so far are&#xD;
      based on one compartment models, which do not reveal if the observed variability in&#xD;
      concentrations is due to changes in PK parameters such as volume of distribution or&#xD;
      clearances. The influence of disease state on these PK parameters has been extensively&#xD;
      described for several antimicrobials in the critically ill patient populations. Although data&#xD;
      on the new IV formulation of posaconazole in this patient population is lacking, there is&#xD;
      evidence from previous PK studies on the oral formulation that PK variability not observed in&#xD;
      healthy study participants was observed in patients with invasive fungal infections, although&#xD;
      it was explained primarily in relation to altered bioavailability from the oral formulation.&#xD;
      In surgical ICU patients low plasma concentration of posaconazole were observed, after&#xD;
      administration via nasogastric tube. Similar findings were reported in general ICU patients.&#xD;
      Although the explanation in these reports was again the irregular absorption, the influence&#xD;
      of other pathologic changes remains to be investigated. A PK evaluation of IV posaconazole in&#xD;
      critically ill patients, not confounded by the absorption factor, would reveal if there is&#xD;
      any pathophysiology-induced PK alteration. Such a study will also give insight into the&#xD;
      dose-exposure relationships and optimal treatment regimen.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 16, 2017</start_date>
  <completion_date type="Actual">May 21, 2017</completion_date>
  <primary_completion_date type="Actual">May 21, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Posaconazole Exposure Described as Area Under the Total Plasma Concentration-time Curve From Time Zero to Infinity After a Single Dose</measure>
    <time_frame>48 hours</time_frame>
    <description>The primary outcome is plasma posaconazole exposure expressed as the area under the total plasma concentration-time curve from time zero to infinity resulting from a single dose of 300 mg of posaconazole administered intravenously.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Posaconazole Exposure Expressed as Area Under the Unbound Concentrations-time Curve From Time Zero to Infinity</measure>
    <time_frame>48 hours</time_frame>
    <description>This is a measure of free posaconazole ( not bound to plasma proteins) exposure in the plasma. This is an important measure of exposure because its the free concentration that distributes into targets sites of infection to produce clinical effect.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Systemic Fungal Infections</condition>
  <arm_group>
    <arm_group_label>Posaconazole</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Posaconazole</intervention_name>
    <description>A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.</description>
    <arm_group_label>Posaconazole</arm_group_label>
    <other_name>Noxafil</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than 18 years&#xD;
&#xD;
          -  Admission for ICU care&#xD;
&#xD;
          -  The presence of suspected or confirmed fungal infection requiring systemic antifungal&#xD;
             therapy&#xD;
&#xD;
          -  Presence of central venous access for drug administration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Prescription of drugs that are known to interact with posaconazole&#xD;
&#xD;
          -  Oral posaconazole use within the last two week prior to enrolment&#xD;
&#xD;
          -  Documented history of drug reaction to the triazole antifungal medications&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jason A Roberts, BPharm</last_name>
    <role>Principal Investigator</role>
    <affiliation>Royal Brisbane and Womens Hospital</affiliation>
  </overall_official>
  <results_reference>
    <citation>Sime FB, Stuart J, Butler J, Starr T, Wallis SC, Pandey S, Lipman J, Roberts JA. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients. Antimicrob Agents Chemother. 2018 May 25;62(6):e00242-18. doi: 10.1128/AAC.00242-18. Print 2018 Jun.</citation>
    <PMID>29581122</PMID>
  </results_reference>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>November 15, 2016</study_first_submitted>
  <study_first_submitted_qc>November 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 18, 2016</study_first_posted>
  <results_first_submitted>May 3, 2018</results_first_submitted>
  <results_first_submitted_qc>June 7, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">July 9, 2018</results_first_posted>
  <last_update_submitted>August 22, 2018</last_update_submitted>
  <last_update_submitted_qc>August 22, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 21, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Royal Brisbane and Women's Hospital</investigator_affiliation>
    <investigator_full_name>Jason Roberts</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycoses</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Posaconazole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>De-identified data for all primary and secondary endpoints will be reported as a collective data set. Individual results will not be reported.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 20, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/34/NCT02968134/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Posaconazole</title>
          <description>The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU&#xD;
Posaconazole: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Posaconazole</title>
          <description>The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU&#xD;
Posaconazole: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="8"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI</title>
          <description>Body mass index calculated in kg/m2</description>
          <units>kg/m^2</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22.6" lower_limit="20.2" upper_limit="29.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Acute Physiology and Chronic Health Evaluation II Score</title>
          <description>Acute Physiology and Chronic Health Evaluation II [APACHE II] score on ICU admission was calculated from 12 routine physiologic measurements using standard approach. APACHE II score ranges from 1 to 71, with higher scores correlating with increased risk of mortality. For a detailed description, please refer to Crit Care Med. 1985 Oct;13(10):818-29.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17" lower_limit="17" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Serum creatinine</title>
          <units>umol/L</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="106" lower_limit="78" upper_limit="179"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Urinary creatinine clearance</title>
          <units>mL/min</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="74" lower_limit="53" upper_limit="109"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Serum albumin</title>
          <units>g/L</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20" lower_limit="18" upper_limit="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ALT</title>
          <description>Alanine transaminase</description>
          <units>IU/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="53" lower_limit="28" upper_limit="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>AST</title>
          <description>Aspartate transaminase</description>
          <units>IU/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47" lower_limit="38" upper_limit="130"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ALP</title>
          <description>Alkaline phosphatase</description>
          <units>IU/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="75" lower_limit="63" upper_limit="108"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Total bilirubin</title>
          <units>umol/L</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11" lower_limit="10" upper_limit="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>INR</title>
          <description>International normalized ratio</description>
          <units>ratio</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.3" lower_limit="1.3" upper_limit="1.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Posaconazole Exposure Described as Area Under the Total Plasma Concentration-time Curve From Time Zero to Infinity After a Single Dose</title>
        <description>The primary outcome is plasma posaconazole exposure expressed as the area under the total plasma concentration-time curve from time zero to infinity resulting from a single dose of 300 mg of posaconazole administered intravenously.</description>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Posaconazole</title>
            <description>The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU&#xD;
Posaconazole: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>Posaconazole Exposure Described as Area Under the Total Plasma Concentration-time Curve From Time Zero to Infinity After a Single Dose</title>
          <description>The primary outcome is plasma posaconazole exposure expressed as the area under the total plasma concentration-time curve from time zero to infinity resulting from a single dose of 300 mg of posaconazole administered intravenously.</description>
          <units>ng*h/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17932" lower_limit="13823" upper_limit="27905"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Posaconazole Exposure Expressed as Area Under the Unbound Concentrations-time Curve From Time Zero to Infinity</title>
        <description>This is a measure of free posaconazole ( not bound to plasma proteins) exposure in the plasma. This is an important measure of exposure because its the free concentration that distributes into targets sites of infection to produce clinical effect.</description>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Posaconazole</title>
            <description>The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU&#xD;
Posaconazole: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>Posaconazole Exposure Expressed as Area Under the Unbound Concentrations-time Curve From Time Zero to Infinity</title>
          <description>This is a measure of free posaconazole ( not bound to plasma proteins) exposure in the plasma. This is an important measure of exposure because its the free concentration that distributes into targets sites of infection to produce clinical effect.</description>
          <units>ng*h/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97.2" lower_limit="72.8" upper_limit="134.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were collected over one and half year of patient enrolment.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Posaconazole</title>
          <description>The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU&#xD;
Posaconazole: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.</description>
        </group>
      </group_list>
      <serious_events>
        <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="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Prof. Jason Roberts</name_or_title>
      <organization>The University of Queensland</organization>
      <phone>+61 7 3646 4108</phone>
      <email>j.roberts2@uq.edu.au</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/NCT02968134
org study id: HREC/16/QRBW/377
nct id: NCT02968134
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to try to find out how critically ill patients receiving the
      anti fungal medication, posaconazole, process it in their body. Investigators would like to
      study if the recommended doses of posaconazole achieve adequate concentrations in the
      patients blood to treat fungal infections.The disease process in critically ill patients can
      profoundly influence the concentration of anti fungal medication in the blood. The process by
      which a drug travels through the body in blood, how it is broken down and removed by the body
      is called pharmacokinetics (PK).

      This information is important to know because if antifungal levels are low in the blood, the
      fungal infection has an opportunity to become resistant to the antifungal medication which
      can lead to the medication being less effective against the fungal infection potentially
      exposing future patients with infection to a limited range of effective antifungals.

      Investigators can measure the PK by taking blood samples at specific times after the anti
      fungal medication is given.

      This study will enroll 8 patients who are admitted to the intensive care unit and are being
      treated with an antifungal medication for a fungal infection. Patients will be consented and
      given a single dose of posaconazole and serial blood samples will be collected just prior to
      the dose and at 15, 45,75 minutes during the infusion and at 3, 5, 8, 12, 18, 24, 30 36 and
      48 hours . Information about the patients stay in the ICU will also be collected including
      blood pressure, temperature, blood test results.
Posaconazole is a new extended spectrum triazole active against a range of yeasts and molds
      including Aspergillus, Candida, Coccidioides, Cryptococcus neoformans, Fusarium, and
      Zygomycetes. It may be used for the prevention of invasive fungal infections in
      immunocompromised patients including febrile neutropenic patients and those receiving
      immunosuppressant drugs for graft-vs-host disease during stem cell transplantation. It may
      also be used for treatment of systemic fungal infections.The use of posaconazole in ICU
      patients has been limited to stable patients to ensure reliable bioavailability from the oral
      formulations. Oral formulations have important limitation in that they cannot be used in
      critically ill patients who may be unable to take oral doses or bioavailability may be
      compromised due to erratic absorption. Recently, an intravenous (IV) formulation has been
      developed to address these limitations. Initial pharmacokinetic (PK) investigations of the IV
      formulation were conducted in hematology patients, with further data in other patient
      populations still forthcoming; particularly in the critically ill where the IV formulation
      would probably be used most frequently.

      Most of the available PK data for posaconazole is from non-critically ill patients who
      received the oral formulation. Although the absorption phase of the kinetics is not relevant
      for the IV formulation, data on the distribution, metabolism and elimination properties would
      still be informative of the IV kinetics. The tissue distribution of posaconazole is extensive
      with a very large volume of distribution owing to its high lipophilicity. It is highly bound
      to plasma proteins (98-99%) and therefore very likely to be affected by the variable changes
      in plasma protein concentration in critically ill patients. The major elimination pathway of
      posaconazoleis through biliary excretion (about 77%) of mainly the unchanged parent compound
      and the rest through renal execration of as a glucuronide conjugate.

      A number of studies have described PK variability of posaconazole due to altered
      absorption/bioavailability which can frequently result in sub-therapeutic plasma
      concentrations, forming strong case for therapeutic drug monitoring. Nonetheless, it is
      unclear whether the observed low concentrations can also be explained, at least in part, by
      other factors such as disease-related PK changes or if the obvious plausibility of altered
      absorption has masked such investigations. Most population PK models described so far are
      based on one compartment models, which do not reveal if the observed variability in
      concentrations is due to changes in PK parameters such as volume of distribution or
      clearances. The influence of disease state on these PK parameters has been extensively
      described for several antimicrobials in the critically ill patient populations. Although data
      on the new IV formulation of posaconazole in this patient population is lacking, there is
      evidence from previous PK studies on the oral formulation that PK variability not observed in
      healthy study participants was observed in patients with invasive fungal infections, although
      it was explained primarily in relation to altered bioavailability from the oral formulation.
      In surgical ICU patients low plasma concentration of posaconazole were observed, after
      administration via nasogastric tube. Similar findings were reported in general ICU patients.
      Although the explanation in these reports was again the irregular absorption, the influence
      of other pathologic changes remains to be investigated. A PK evaluation of IV posaconazole in
      critically ill patients, not confounded by the absorption factor, would reveal if there is
      any pathophysiology-induced PK alteration. Such a study will also give insight into the
      dose-exposure relationships and optimal treatment regimen.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Posaconazole Exposure Described as Area Under the Total Plasma Concentration-time Curve From Time Zero to Infinity After a Single Dose
time frame: 48 hours
description: The primary outcome is plasma posaconazole exposure expressed as the area under the total plasma concentration-time curve from time zero to infinity resulting from a single dose of 300 mg of posaconazole administered intravenously.
measure: Posaconazole Exposure Expressed as Area Under the Unbound Concentrations-time Curve From Time Zero to Infinity
time frame: 48 hours
description: This is a measure of free posaconazole ( not bound to plasma proteins) exposure in the plasma. This is an important measure of exposure because its the free concentration that distributes into targets sites of infection to produce clinical effect.
arm group label: Posaconazole
arm group type: Other
description: The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU
intervention type: Drug
intervention name: Posaconazole
description: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.
arm group label: Posaconazole
other name: Noxafil
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jason A Roberts, BPharm
role: Principal Investigator
affiliation: Royal Brisbane and Womens Hospital
citation: Sime FB, Stuart J, Butler J, Starr T, Wallis SC, Pandey S, Lipman J, Roberts JA. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients. Antimicrob Agents Chemother. 2018 May 25;62(6):e00242-18. doi: 10.1128/AAC.00242-18. Print 2018 Jun.
PMID: 29581122
responsible party type: Principal Investigator
investigator affiliation: Royal Brisbane and Women's Hospital
investigator full name: Jason Roberts
investigator title: Professor
mesh term: Mycoses
mesh term: Posaconazole
sharing ipd: No
ipd description: De-identified data for all primary and secondary endpoints will be reported as a collective data set. Individual results will not be reported.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 