<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/NCT03033394</url>
  </required_header>
  <id_info>
    <org_study_id>207217</org_study_id>
    <secondary_id>16/LO/2179</secondary_id>
    <secondary_id>33017</secondary_id>
    <nct_id>NCT03033394</nct_id>
  </id_info>
  <brief_title>Beta-lactam Pharmacokinetics in Secondary Care</brief_title>
  <official_title>Defining Adult Beta-lactam Antimicrobial Pharmacokinetics Across the Secondary Care Setting</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide&#xD;
      antimicrobial agents, given fears over the narrow therapeutic window of these agents and the&#xD;
      serious adverse events associated with toxicity. However, in critical care the role of TDM&#xD;
      for optimisation of therapy has been demonstrated to help optimise dosing of patients who&#xD;
      tend to have variable pharmacokinetic parameters (J. A. Roberts et al,). This is of growing&#xD;
      importance given that low concentrations of antimicrobial agents, below a micro-organisms&#xD;
      minimum inhibitory concentration (MIC) is believed to be a major driver of AMR. The&#xD;
      investigators set out to explore whether similar observations in PK-PD target variability are&#xD;
      currently being observed across the secondary care setting (outside of critical care) and&#xD;
      whether these appear to be impacting on clinical outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      STUDY PARTICIPANTS&#xD;
&#xD;
        -  Participants receiving oral or intravenous therapy will be included in this study.&#xD;
&#xD;
        -  Drug level sampling will be undertaken once the participant is at steady state (after at&#xD;
           least 5 doses have been administered to those on treatment).&#xD;
&#xD;
        -  All patients will be consented using the participation information leaflet and consent&#xD;
           form provided in appendix 1.&#xD;
&#xD;
      DRUG LEVEL SAMPLING&#xD;
&#xD;
        -  Patients will be identified for inclusion, and researchers will discuss inclusion in the&#xD;
           study with the patient and provide clinical information for them to consider.&#xD;
           Individuals will be recruited from all areas of secondary care (including, general&#xD;
           medicine, general surgery, augmented care, and out-patient parenteral antimicrobial&#xD;
           therapy [OPAT]).&#xD;
&#xD;
        -  They will then be consented by researchers after being given at least 24 hours to&#xD;
           consider this information and as long as the patient has expressed interest in&#xD;
           participating to their treating physician.&#xD;
&#xD;
        -  This will include permission for basic, anonymised demographic and clinical data to be&#xD;
           collected related to the patients infection, for which they are receiving antimicrobial&#xD;
           therapy.&#xD;
&#xD;
        -  An extra 3mLs of blood will be collected during the patient's routine daily phlebotomy&#xD;
           round following their consent. They will be enrolled for up to 72 hours or two days of&#xD;
           routine blood tests (whichever is shorter). Up to 10 samples may be taken during the 2&#xD;
           days the patient is enrolled, depending on the number of routine blood tests the patient&#xD;
           receives during that day. No more than 3mLs will be taken per each routine blood sample.&#xD;
           For example, if the individuals will only have routine blood tests taken at 8am on day 1&#xD;
           and day 2. Then only two extra samples will be taken (3mLs on D1 and 3mLs on D2).&#xD;
&#xD;
        -  The time they received their dose of antimicrobials, the length of infusion time (if&#xD;
           available), and time the sample was collected will all be recorded.&#xD;
&#xD;
        -  PK/PD indices for evaluation will be calculated post-hoc during&#xD;
           pharmacokinetic-pharmacodynamic analysis. TDM sampling can occur at any time during the&#xD;
           dosing schedule (in line with routine blood testing).&#xD;
&#xD;
        -  A standard operating procedure for this study can be found in appendix 3.&#xD;
&#xD;
      SAMPLE PREPARATION AND ANALYSIS&#xD;
&#xD;
        -  All blood samples will be allowed to clot and placed on ice. They will be centrifuged at&#xD;
           2,400rpm for 10 minutes. Sera from each sample will be separated into three vials and&#xD;
           stored at -80C.&#xD;
&#xD;
        -  Beta-lactam concentrations will be measured using validated high-performance liquid&#xD;
           chromatography methods.&#xD;
&#xD;
        -  Samples will be stored for up to three years post completion of data collection.&#xD;
&#xD;
             -  Consent will be gained for samples to be used for calibration of electrochemical&#xD;
                sensors in ex-vivo studies. This will be performed within 90 days of the samples&#xD;
                being collected.&#xD;
&#xD;
      PHARMCOKINETIC-PHARMACODYNAMIC MODELLING&#xD;
&#xD;
        -  Data will be anonymised and analysed using Pmetrics in R.&#xD;
&#xD;
        -  Different pharmacokinetic models will be explored using in built statistical analysis&#xD;
           options and visual predictive checks.&#xD;
&#xD;
        -  Pharmacodynamic models will then be incorporated into the model using evidence&#xD;
           identified in the literature for selection of parameters.&#xD;
&#xD;
        -  Monte Carlo simulation will then be used to for simulation of target attainments and&#xD;
           analysis of pharmacodynamic outcomes&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 12, 2017</start_date>
  <completion_date type="Actual">August 1, 2019</completion_date>
  <primary_completion_date type="Actual">August 1, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT&gt;MIC)</measure>
    <time_frame>Two to 10 samples taken during the first 120 hours of antimicrobial therapy</time_frame>
    <description>Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">65</enrollment>
  <condition>Pharmacokinetics</condition>
  <condition>Beta Lactam Adverse Reaction</condition>
  <condition>Penicillin Allergy</condition>
  <arm_group>
    <arm_group_label>Beta-lactam antibiotic</arm_group_label>
    <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Beta-lactam antibiotic</intervention_name>
    <description>Routine clinical dosing</description>
    <arm_group_label>Beta-lactam antibiotic</arm_group_label>
    <other_name>Penicillin</other_name>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Participants from a non-critical care setting will be recruited after receiving at least 5&#xD;
        doses of target antimicrobial. Participants receiving oral and intravenous therapy will be&#xD;
        eligible.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult subjects over 18 years old&#xD;
&#xD;
          -  Capacity to consent to participation&#xD;
&#xD;
          -  Receiving target antimicrobial (amoxicillin, amoxcillin-clavulanate, cefuroxime,&#xD;
             ceftriaxone, flucloxacillin, meropenem, piperacillin-tazobactam) for at least 5 doses&#xD;
             prior to sampling&#xD;
&#xD;
          -  Appropriate venous access (or for venous access to be gained)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Children under 18 years old&#xD;
&#xD;
          -  Lacking capacity or prisoner&#xD;
&#xD;
          -  Anaemia or bleeding disorder, deemed significant by the patients physician&#xD;
&#xD;
          -  Patient's physician deems that they are not suitable for inclusion in the study&#xD;
&#xD;
          -  Patients unlikely to be receiving agent for study period&#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>Alison H Holmes, MD MPH MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Health Protection Research Unit in HCAI &amp; AMR</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hammersmith Hospital</name>
      <address>
        <city>London</city>
        <zip>W12 0HS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>January 19, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <results_first_submitted>August 3, 2020</results_first_submitted>
  <results_first_submitted_qc>August 4, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">August 30, 2021</results_first_posted>
  <last_update_submitted>August 4, 2021</last_update_submitted>
  <last_update_submitted_qc>August 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Penicillins</keyword>
  <keyword>Drug Monitoring</keyword>
  <keyword>Pharmacokinetics</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anti-Bacterial Agents</mesh_term>
    <mesh_term>Penicillins</mesh_term>
    <mesh_term>Lactams</mesh_term>
    <mesh_term>beta-Lactams</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 31, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03033394/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Beta-lactam Antibiotic</title>
          <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Completed Sampling</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="65"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="65"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Completed Pharmacokinetic Analysis</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="65"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="59"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Missing data</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Oral dosing not incorporated into pharmacokinetic model</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Level taken at incorrect time</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Pharmacokinetic soffware unable to generate predicted values</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Completed Final Analysis</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="59"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>1 participant excluded from final analysis as an outlier (&gt;1.5 x interquartile range)</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Beta-lactam Antibiotic</title>
          <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="65"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <population>6 patients excluded from pharmacokinetic analysis:&#xD;
1 participant missing data&#xD;
3 oral dosing could not be integrated into model&#xD;
1 level taken incorrect time&#xD;
1 model unable to calculate individual predicted value</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="59"/>
                  </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="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <population>6 patients excluded from pharmacokinetic analysis:&#xD;
1 participant missing data&#xD;
3 oral dosing could not be integrated into model&#xD;
1 level taken incorrect time&#xD;
1 model unable to calculate individual predicted value</population>
          <units>years</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="59"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62" lower_limit="48" upper_limit="72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>6 patients excluded from pharmacokinetic analysis:&#xD;
1 participant missing data&#xD;
3 oral dosing could not be integrated into model&#xD;
1 level taken incorrect time&#xD;
1 model unable to calculate individual predicted value</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="59"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <population>6 patients excluded from pharmacokinetic analysis:&#xD;
1 participant missing data&#xD;
3 oral dosing could not be integrated into model&#xD;
1 level taken incorrect time&#xD;
1 model unable to calculate individual predicted value</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="59"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT&gt;MIC)</title>
        <description>Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.</description>
        <time_frame>Two to 10 samples taken during the first 120 hours of antimicrobial therapy</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Amoxicillin</title>
            <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
          </group>
          <group group_id="O2">
            <title>Co-amoxiclav</title>
            <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
          </group>
          <group group_id="O3">
            <title>Ceftriaxone</title>
            <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
          </group>
          <group group_id="O4">
            <title>Flucloxacillin</title>
            <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
          </group>
          <group group_id="O5">
            <title>Meropenem</title>
            <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
          </group>
          <group group_id="O6">
            <title>Piperacillin-tazobactam</title>
            <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
          </group>
        </group_list>
        <measure>
          <title>Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT&gt;MIC)</title>
          <description>Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.</description>
          <units>unitless</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="3"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="14"/>
                <count group_id="O5" value="13"/>
                <count group_id="O6" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.457" lower_limit="0.417" upper_limit="0.479"/>
                    <measurement group_id="O2" value="0.429" lower_limit="0.417" upper_limit="0.479"/>
                    <measurement group_id="O3" value="0.747" lower_limit="0.741" upper_limit="1.04"/>
                    <measurement group_id="O4" value="0.417" lower_limit="0.285" upper_limit="0.700"/>
                    <measurement group_id="O5" value="0.333" lower_limit="0.319" upper_limit="0.345"/>
                    <measurement group_id="O6" value="1.63" lower_limit="0.971" upper_limit="1.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Mortality outcome collected from time target antimicrobial commenced until time target antimicrobial stopped. This was median 9 days (interquartile range 6-13 days)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Beta-lactam Antibiotic</title>
          <description>Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.&#xD;
Beta-lactam antibiotic: Routine clinical dosing</description>
        </group>
      </group_list>
      <serious_events>
        <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="59"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
              </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="59"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>
    <point_of_contact>
      <name_or_title>Richard Wilson</name_or_title>
      <organization>Imperial College London</organization>
      <phone>02033132732</phone>
      <email>richard.wilson@imperial.ac.uk</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/NCT03033394
org study id: 207217
secondary id: 16/LO/2179
secondary id: 33017
nct id: NCT03033394
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide
      antimicrobial agents, given fears over the narrow therapeutic window of these agents and the
      serious adverse events associated with toxicity. However, in critical care the role of TDM
      for optimisation of therapy has been demonstrated to help optimise dosing of patients who
      tend to have variable pharmacokinetic parameters (J. A. Roberts et al,). This is of growing
      importance given that low concentrations of antimicrobial agents, below a micro-organisms
      minimum inhibitory concentration (MIC) is believed to be a major driver of AMR. The
      investigators set out to explore whether similar observations in PK-PD target variability are
      currently being observed across the secondary care setting (outside of critical care) and
      whether these appear to be impacting on clinical outcomes.
STUDY PARTICIPANTS

        -  Participants receiving oral or intravenous therapy will be included in this study.

        -  Drug level sampling will be undertaken once the participant is at steady state (after at
           least 5 doses have been administered to those on treatment).

        -  All patients will be consented using the participation information leaflet and consent
           form provided in appendix 1.

      DRUG LEVEL SAMPLING

        -  Patients will be identified for inclusion, and researchers will discuss inclusion in the
           study with the patient and provide clinical information for them to consider.
           Individuals will be recruited from all areas of secondary care (including, general
           medicine, general surgery, augmented care, and out-patient parenteral antimicrobial
           therapy [OPAT]).

        -  They will then be consented by researchers after being given at least 24 hours to
           consider this information and as long as the patient has expressed interest in
           participating to their treating physician.

        -  This will include permission for basic, anonymised demographic and clinical data to be
           collected related to the patients infection, for which they are receiving antimicrobial
           therapy.

        -  An extra 3mLs of blood will be collected during the patient's routine daily phlebotomy
           round following their consent. They will be enrolled for up to 72 hours or two days of
           routine blood tests (whichever is shorter). Up to 10 samples may be taken during the 2
           days the patient is enrolled, depending on the number of routine blood tests the patient
           receives during that day. No more than 3mLs will be taken per each routine blood sample.
           For example, if the individuals will only have routine blood tests taken at 8am on day 1
           and day 2. Then only two extra samples will be taken (3mLs on D1 and 3mLs on D2).

        -  The time they received their dose of antimicrobials, the length of infusion time (if
           available), and time the sample was collected will all be recorded.

        -  PK/PD indices for evaluation will be calculated post-hoc during
           pharmacokinetic-pharmacodynamic analysis. TDM sampling can occur at any time during the
           dosing schedule (in line with routine blood testing).

        -  A standard operating procedure for this study can be found in appendix 3.

      SAMPLE PREPARATION AND ANALYSIS

        -  All blood samples will be allowed to clot and placed on ice. They will be centrifuged at
           2,400rpm for 10 minutes. Sera from each sample will be separated into three vials and
           stored at -80C.

        -  Beta-lactam concentrations will be measured using validated high-performance liquid
           chromatography methods.

        -  Samples will be stored for up to three years post completion of data collection.

             -  Consent will be gained for samples to be used for calibration of electrochemical
                sensors in ex-vivo studies. This will be performed within 90 days of the samples
                being collected.

      PHARMCOKINETIC-PHARMACODYNAMIC MODELLING

        -  Data will be anonymised and analysed using Pmetrics in R.

        -  Different pharmacokinetic models will be explored using in built statistical analysis
           options and visual predictive checks.

        -  Pharmacodynamic models will then be incorporated into the model using evidence
           identified in the literature for selection of parameters.

        -  Monte Carlo simulation will then be used to for simulation of target attainments and
           analysis of pharmacodynamic outcomes
observational model: Cohort
time perspective: Prospective
measure: Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT>MIC)
time frame: Two to 10 samples taken during the first 120 hours of antimicrobial therapy
description: Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.
arm group label: Beta-lactam antibiotic
description: Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.
intervention type: Drug
intervention name: Beta-lactam antibiotic
description: Routine clinical dosing
arm group label: Beta-lactam antibiotic
other name: Penicillin
Plasma
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alison H Holmes, MD MPH MBBS
role: Principal Investigator
affiliation: Health Protection Research Unit in HCAI & AMR
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Anti-Bacterial Agents
mesh term: Penicillins
mesh term: Lactams
mesh term: beta-Lactams
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 