<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/NCT02213796</url>
  </required_header>
  <id_info>
    <org_study_id>MEROICU14</org_study_id>
    <nct_id>NCT02213796</nct_id>
  </id_info>
  <brief_title>Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem During the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units</brief_title>
  <official_title>Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem During the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sutep Jaruratanasirikul</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Prince of Songkla University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Prince of Songkla University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, noncomparative study to assess the pharmacodynamics of meropenem&#xD;
      during early phase of severe sepsis and septic shock in critically ill patients in an&#xD;
      intensive care unit.&#xD;
&#xD;
      Clinical and laboratory data such as age,sex, body weight, electrolyte, vital signs, APACHE&#xD;
      II score, SOFA score, BUN, Cr and blood culture will be collected.&#xD;
&#xD;
      Twelve patients will be enrolled in this study. Meropenem pharmacokinetic will be carried out&#xD;
      during the first and second dose after 1g meropenem administration. Blood samples&#xD;
      (approximately 3 ml) will be obtained by direct venepuncture at the following time: 0, 0.25,&#xD;
      0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 8, 8.5, 9, 9.5, 10, 12, 14 and 16 h.&#xD;
&#xD;
      Meropenem assays will be performed by modified method of Ozkan et al. (Biomed. Chromatogr.,&#xD;
      2001).&#xD;
&#xD;
      The pharmacokinetics of meropenem will be modelled from concentration-time profile using&#xD;
      compartmental model. Monte Carlo simulation to assess PK/PD index as 40% and 100% T&gt;MIC will&#xD;
      be conducted and the results will be reported as % PTA (Probability Target Attainment) and&#xD;
      %CFR (Cumulative Faction Response)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction:&#xD;
&#xD;
      Severe sepsis/septic shock are one of the most important reasons for admission the&#xD;
      critically-ill patient to Intensive Care Units (ICU) and remaining a major causes of high&#xD;
      mortality. Evidently, the fluctuation in pathophysiology, particularly during early phase, of&#xD;
      this condition may result in PK alteration and lead to the inadequate antibiotic dosed of&#xD;
      standard treatment. Therefore, thearly phase treatment with an appropriate antimicrobial&#xD;
      doses that achieved pharmacodynamic target for antimicrobial therapy have been the crucial&#xD;
      factor for therapeutic.&#xD;
&#xD;
      Meropenem, a carbapenem antibiotic, is a β-lactam antimicrobial agent with a broad spectrum&#xD;
      of activity, coverage of gram-negative bacteria including highly resistant pathogens for&#xD;
      instance ESBL-producing or AmpC-mediated b-lactamase producing Enterobacteriaceae. This&#xD;
      agent, in common with other β-lactams, is characterized by time-dependent antimicrobial&#xD;
      activity, and the exposure time during which the free drug concentrations remains above the&#xD;
      minimum inhibitory concentration (T&gt;MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) index&#xD;
      that best correlates with efficacy. The majority of previous PK/PDs studies on β-lactams in&#xD;
      critically ill patients were mostly conducted in the steady-state period of treatment in&#xD;
      which during the early phase of severe sepsis/septic shock was still lacking.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      To study the population PK of meropenem and assess the probability of target attainment (PTA)&#xD;
      of meropenem inthe initial phases of severe sepsis or septic shock patients in order to be&#xD;
      able to optimize dosing recommendations.&#xD;
&#xD;
      Clinical and laboratory data:&#xD;
&#xD;
      Age, sex, body weight, electrolite, vitalsigns, APACHAE II score, BUN, Cr, blood culture&#xD;
&#xD;
      Drug preparation and administration:&#xD;
&#xD;
      The dosage of meropenem was 1-h infusion of 1g diluted in 100 mL of normal saline solution&#xD;
      via infusion pump at a constant flow rate every 8 h (q8h) for 16 hours.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      Prospective non-comparative studyof 9 patients during the initial 24 h of severe sepsis or&#xD;
      septic shock. Each subject received a 1-h infusion of 1 g q8h of meropenem for 16 hrs. Monte&#xD;
      Carlo simulation were attempted to analyze the pharmacokinetics of experimental data.&#xD;
&#xD;
      Sample collection:&#xD;
&#xD;
      Meropenem PK studies were carried out during the administration of the first and second dose&#xD;
      of meropenem (0-16 h after the start of administration of meropenem). Blood samples (ca. 3&#xD;
      mL) were obtained by direct venipuncture at the following times: shortly before (time 0) and&#xD;
      then at 0.25, 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 8, 8.5, 9, 9.5, 10, 12, 14 and 16 h after&#xD;
      the start of administration of meropenem. All blood samples were added to a heparinized tube,&#xD;
      were immediately stored on ice and were centrifuged at 2000 × g at 4◦C for 10 min within 5&#xD;
      min. All plasma samples were stored at -80◦C until analysis within 1 week.&#xD;
&#xD;
      Moropenem assay:&#xD;
&#xD;
      The meropenem assays by method of Ozkan et al. (Biomed Chromatogr, 2001) will be performed at&#xD;
      Department of Medicine, Faculty of Medicine.&#xD;
&#xD;
      Duration of study:&#xD;
&#xD;
      Patients will receive a 1-h infusion of 1 g q8h of meropenem for 16 hrs.&#xD;
&#xD;
      Pharmacokinetic and pharmacodynamic analysis:&#xD;
&#xD;
      Concentration of meropenem in plasma will be simulated in Monte Carlo technique to get PK/PD&#xD;
      index (40% and 80% PTA)&#xD;
&#xD;
      Sample size: Nine patients with severe sepsis and septic shock.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2013</start_date>
  <completion_date type="Actual">December 2013</completion_date>
  <primary_completion_date type="Actual">December 2013</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>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Concentration of meropenem in plasma</measure>
    <time_frame>16 hour after first dose</time_frame>
    <description>Concentration of meropenem inplasma will be simulated in Monte Carli simulation to assess PK/PD index as 40% and 100 T&gt;MIC and will be reported as %PTA.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Initial Phase of Severe Sepsis and Septic Shock</condition>
  <arm_group>
    <arm_group_label>1h infusion of 1 g meropenem</arm_group_label>
    <arm_group_type>Other</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Meropenem</intervention_name>
    <arm_group_label>1h infusion of 1 g meropenem</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient age &gt; 18 years&#xD;
&#xD;
          2. Patients who diagnosed as severe sepsis or septic shock, either at admission or during&#xD;
             the ICU stay. Sepsis is the systemic response to infections defined by two or more of&#xD;
             the following conditions: body temperature of &gt;38 oC or &lt;36 oC; heart rate of &gt; 90&#xD;
             beats per min; respiratory rate of &gt;20 breaths per min or a PaCO2 of &lt;32 mmHg; or&#xD;
             leucocyte count &gt;12,000 cell/mm3, &lt;4,000 cell/mm3 or 10% immature (band) forms. Severe&#xD;
             sepsis is defined by sepsis associated with organ dysfunction, hypoperfusion, or&#xD;
             hypotension (systolic arterial pressure &lt;90 mmHg, mean arterial pressure &lt;70 mmHg or a&#xD;
             reduction of ≥40 mmHg from baseline). Septic shock is defined by severe sepsis&#xD;
             associated with hypotension despite adequate fluid resuscitation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients who are pregnant.&#xD;
&#xD;
          2. Patients who have documented hypersensitivity to carbapenems.&#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>Sutep Jaruratanasirikul, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Prince of Songkla University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Prince of Songkla University</name>
      <address>
        <city>Hat Yai</city>
        <state>Songkhla</state>
        <zip>90110</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Thailand</country>
  </location_countries>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 8, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 11, 2014</study_first_posted>
  <last_update_submitted>August 8, 2014</last_update_submitted>
  <last_update_submitted_qc>August 8, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 11, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Prince of Songkla University</investigator_affiliation>
    <investigator_full_name>Sutep Jaruratanasirikul</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>meropenem, early phase, severe sepsis and septic shock, critically ill, population pharmacokinetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Shock</mesh_term>
    <mesh_term>Critical Illness</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Meropenem</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02213796
org study id: MEROICU14
nct id: NCT02213796
lead sponsor: 
collaborator: 
has dmc: No
This is a prospective, noncomparative study to assess the pharmacodynamics of meropenem
      during early phase of severe sepsis and septic shock in critically ill patients in an
      intensive care unit.

      Clinical and laboratory data such as age,sex, body weight, electrolyte, vital signs, APACHE
      II score, SOFA score, BUN, Cr and blood culture will be collected.

      Twelve patients will be enrolled in this study. Meropenem pharmacokinetic will be carried out
      during the first and second dose after 1g meropenem administration. Blood samples
      (approximately 3 ml) will be obtained by direct venepuncture at the following time: 0, 0.25,
      0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 8, 8.5, 9, 9.5, 10, 12, 14 and 16 h.

      Meropenem assays will be performed by modified method of Ozkan et al. (Biomed. Chromatogr.,
      2001).

      The pharmacokinetics of meropenem will be modelled from concentration-time profile using
      compartmental model. Monte Carlo simulation to assess PK/PD index as 40% and 100% T>MIC will
      be conducted and the results will be reported as % PTA (Probability Target Attainment) and
      %CFR (Cumulative Faction Response)
Introduction:

      Severe sepsis/septic shock are one of the most important reasons for admission the
      critically-ill patient to Intensive Care Units (ICU) and remaining a major causes of high
      mortality. Evidently, the fluctuation in pathophysiology, particularly during early phase, of
      this condition may result in PK alteration and lead to the inadequate antibiotic dosed of
      standard treatment. Therefore, thearly phase treatment with an appropriate antimicrobial
      doses that achieved pharmacodynamic target for antimicrobial therapy have been the crucial
      factor for therapeutic.

      Meropenem, a carbapenem antibiotic, is a β-lactam antimicrobial agent with a broad spectrum
      of activity, coverage of gram-negative bacteria including highly resistant pathogens for
      instance ESBL-producing or AmpC-mediated b-lactamase producing Enterobacteriaceae. This
      agent, in common with other β-lactams, is characterized by time-dependent antimicrobial
      activity, and the exposure time during which the free drug concentrations remains above the
      minimum inhibitory concentration (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) index
      that best correlates with efficacy. The majority of previous PK/PDs studies on β-lactams in
      critically ill patients were mostly conducted in the steady-state period of treatment in
      which during the early phase of severe sepsis/septic shock was still lacking.

      Objectives:

      To study the population PK of meropenem and assess the probability of target attainment (PTA)
      of meropenem inthe initial phases of severe sepsis or septic shock patients in order to be
      able to optimize dosing recommendations.

      Clinical and laboratory data:

      Age, sex, body weight, electrolite, vitalsigns, APACHAE II score, BUN, Cr, blood culture

      Drug preparation and administration:

      The dosage of meropenem was 1-h infusion of 1g diluted in 100 mL of normal saline solution
      via infusion pump at a constant flow rate every 8 h (q8h) for 16 hours.

      Study design:

      Prospective non-comparative studyof 9 patients during the initial 24 h of severe sepsis or
      septic shock. Each subject received a 1-h infusion of 1 g q8h of meropenem for 16 hrs. Monte
      Carlo simulation were attempted to analyze the pharmacokinetics of experimental data.

      Sample collection:

      Meropenem PK studies were carried out during the administration of the first and second dose
      of meropenem (0-16 h after the start of administration of meropenem). Blood samples (ca. 3
      mL) were obtained by direct venipuncture at the following times: shortly before (time 0) and
      then at 0.25, 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 8, 8.5, 9, 9.5, 10, 12, 14 and 16 h after
      the start of administration of meropenem. All blood samples were added to a heparinized tube,
      were immediately stored on ice and were centrifuged at 2000 × g at 4◦C for 10 min within 5
      min. All plasma samples were stored at -80◦C until analysis within 1 week.

      Moropenem assay:

      The meropenem assays by method of Ozkan et al. (Biomed Chromatogr, 2001) will be performed at
      Department of Medicine, Faculty of Medicine.

      Duration of study:

      Patients will receive a 1-h infusion of 1 g q8h of meropenem for 16 hrs.

      Pharmacokinetic and pharmacodynamic analysis:

      Concentration of meropenem in plasma will be simulated in Monte Carlo technique to get PK/PD
      index (40% and 80% PTA)

      Sample size: Nine patients with severe sepsis and septic shock.
allocation: N/A
intervention model: Single Group Assignment
masking: None (Open Label)
measure: Concentration of meropenem in plasma
time frame: 16 hour after first dose
description: Concentration of meropenem inplasma will be simulated in Monte Carli simulation to assess PK/PD index as 40% and 100 T>MIC and will be reported as %PTA.
arm group label: 1h infusion of 1 g meropenem
arm group type: Other
intervention type: Drug
intervention name: Meropenem
arm group label: 1h infusion of 1 g meropenem
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sutep Jaruratanasirikul, MD
role: Principal Investigator
affiliation: Prince of Songkla University
facility: 
country: Thailand
responsible party type: Sponsor-Investigator
investigator affiliation: Prince of Songkla University
investigator full name: Sutep Jaruratanasirikul
investigator title: Principal investigator
mesh term: Sepsis
mesh term: Toxemia
mesh term: Shock, Septic
mesh term: Shock
mesh term: Critical Illness
mesh term: Meropenem