<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/NCT03025841</url>
  </required_header>
  <id_info>
    <org_study_id>CEFTAREA</org_study_id>
    <nct_id>NCT03025841</nct_id>
  </id_info>
  <brief_title>Population Pharmacokinetic (PK) Study of Zinforo (Ceftaroline) in Critical Care Patients With Early-onset Pneumonia and Normal or Augmented Renal Clearance</brief_title>
  <acronym>CEFTAREA</acronym>
  <official_title>Population Pharmacokinetic (PK) Study of Zinforo (Ceftaroline) in Critical Care Patients With Early-onset Pneumonia and Normal or Augmented Renal Clearance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Poitiers University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Poitiers University Hospital</source>
  <brief_summary>
    <textblock>
      Pneumonia is the most frequent infection in critically ill patients and remains a significant&#xD;
      challenge to intensivists world-wide due to persisting high mortality and morbidity.&#xD;
      Compelling evidence suggests that appropriate antibiotic therapy remains the most important&#xD;
      intervention to improve patients' outcome, including the administration of a suitable&#xD;
      molecule at an optimized dosage regimen. A vast array of pathophysiological changes can occur&#xD;
      in critically ill patients that can complicate antibiotic dosing. Knowledge of the&#xD;
      pharmacokinetic and pharmacodynamic properties of the antibiotics used for the management of&#xD;
      critically ill patients is essential for selecting the antibiotic dosing regimens, which will&#xD;
      optimize patient outcomes. Changes in volume of distribution (Vd) and clearance (CL) of&#xD;
      antibiotics have been noted in these patients, which may affect the antibiotic concentration&#xD;
      at the target site. It follows that the pharmacodynamic parameters that determine antibiotic&#xD;
      efficacy, which can vary between antibiotic classes, may also be affected. Optimization of&#xD;
      these parameters is necessary to maximize the rate of response through patient recovery and&#xD;
      minimized antibiotic resistance.&#xD;
&#xD;
      In a multicenter observational study in critically ill patients with normal plasma renal&#xD;
      indices at admission, about 65% of patients manifested augmented creatinine clearance on at&#xD;
      least one occasion in the first seven study days. Augmented creatinine clearance may&#xD;
      significantly impact drug pharmacokinetics for a variety of renally eliminated&#xD;
      pharmaceuticals (such as low-molecular weight heparins, aminoglycosides, glycopeptides, and&#xD;
      β-lactams), leading to subtherapeutic concentrations and potentially adverse clinical&#xD;
      outcomes. Currently little data exist that describe the consequences of augmented creatinine&#xD;
      clearance on antibiotics PK.&#xD;
&#xD;
      Ceftaroline (600 mg bid) is a cephalosporin with expanded gram-positive activity, including&#xD;
      MRSA and penicillin-resistant streptococcus, which was approved by the US Food and Drug&#xD;
      Administration (FDA) on October 29, 2010 for the treatment of acute bacterial SSSIs and&#xD;
      community-acquired bacterial pneumonia. Ceftaroline showed also good activity against some of&#xD;
      the common gram-negative respiratory pathogens (eg, Haemophilus influenzae, Moraxella&#xD;
      catarrhalis, Neisseria meningitidis, and Pasteurella multocida). However, it does not display&#xD;
      clinically relevant activity against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or&#xD;
      Acinetobacter baumannii. Ceftaroline also lacks activity against gram-negative organisms with&#xD;
      extended-spectrum β-lactamases. Importantly, because ceftaroline appears to induce AmpC&#xD;
      β-lactamases despite MIC values in susceptible range, ittheoretically should be avoided in&#xD;
      gram-negative bacteria known to harbor inducible AmpC β-lactamases (eg, Serratia, Proteus,&#xD;
      Citrobacter, Morganella, Enterobacter, Providencia, and P. aeruginosa). In patients,&#xD;
      ceftaroline is given as a prodrug, ceftaroline fosamil. After intravenous administration, the&#xD;
      prodrug is rapidly transformed by plasma phosphatase enzymes to its bioactive metabolite. The&#xD;
      pharmacokinetics of ceftaroline has been evaluated in single and multiple dose studies in&#xD;
      healthy volunteers, in subjects with various degrees of renal impairment and in healthy&#xD;
      elderly subjects. The volume of distribution is equal to 20.3 L, which corresponds to&#xD;
      extracellular fluid volume. The protein binding is low (20%). The main route of elimination&#xD;
      is via renal excretion, with a clearance estimated to160 mL/min close to the creatinine&#xD;
      clearance. The elimination half-live is 2.6 h in adults with normal renal function.&#xD;
      Unfortunately, no PK study has been performed in infected critically ill patients with&#xD;
      augmented creatinine clearance. The best PK-PD index predicting drug efficacy is %Time&gt;CMI. A&#xD;
      bacteriostatic effect is achieved when free drug concentrations exceed the MIC for 30 to 40%&#xD;
      of the dose administration interval (30 to 40%T&gt;MIC). Near maximum organism kill is achieved&#xD;
      at 50 to 60%T&gt;MIC (30%T&gt;MIC for Staphylococcus aureus).&#xD;
&#xD;
      This project aims to characterize ceftaroline PK in patients with early-onset pneumonia and&#xD;
      augmented creatinine clearance. The choice of ceftaroline is justified by its spectrum&#xD;
      suitable for micro-organisms commonly encountered in early onset pneumonia, including&#xD;
      methicillin-resistant Staphylococcus aureus. Secondary main objective is to predict the&#xD;
      probably of reaching PK-PD targets using Monte Carlo simulations under various scenario in&#xD;
      order to identify optimal ceftaroline administration schemes in critical care patients with&#xD;
      various degrees of renal impairment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2016</start_date>
  <completion_date type="Actual">June 2018</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>Phase 1</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Minimum plasma concentration of Ceftaroline</measure>
    <time_frame>Day 6</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum plasma concentration of Ceftaroline</measure>
    <time_frame>Day 6</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Volume of distribution of Ceftaroline in plasma</measure>
    <time_frame>Day 6</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Clearance of Ceftaroline in plasma</measure>
    <time_frame>Day 6</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Elimination half life of Ceftaroline in plasma</measure>
    <time_frame>Day 6</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic measures outcomes to obtain the dosing regimens through the monte carlo simulation.</measure>
    <time_frame>Day 6</time_frame>
    <description>in at least 90% of simulated subjects for minimal inhibitory concentration from 0.008 to 32 mg/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical efficacy during Ceftaroline treatment and two weeks after end of it</measure>
    <time_frame>Day 28</time_frame>
    <description>Patients will be considered to have clinical failure if they will have no response to the study drug on the basis of ongoing signs and symptoms of infection. Otherwise, patients will be considered to have clinical success</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation by adverse events and serious adverse events collection</measure>
    <time_frame>One month following the last administration</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Pneumonia</condition>
  <arm_group>
    <arm_group_label>Ceftaroline</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients receive Ceftaroline 600mg BID</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ceftaroline</intervention_name>
    <arm_group_label>Ceftaroline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Hospitalized in ICU&#xD;
&#xD;
          -  Under mechanical ventilation&#xD;
&#xD;
          -  Developing early-onset (during the seven days following hospital admission) pneumonia&#xD;
             caused by Gram positive and/or Gram negative bacteria.&#xD;
&#xD;
          -  Having an augmented or normal renal clearance defined by a directly measured&#xD;
             creatinine clearance, using MD-RD:&#xD;
&#xD;
               -  normal clearance: between 80 and 130 mL/min/1.73m²&#xD;
&#xD;
               -  augmented clearance: more than or equal to 130 mL/min/1.73m²&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Having one or more risk factors of multi drug resistant bacteria:&#xD;
&#xD;
               -  antibiotic treatment in last 3 months&#xD;
&#xD;
               -  high level resistance in the unit&#xD;
&#xD;
               -  immunosuppression&#xD;
&#xD;
               -  one or more pneumonia risks factors, whose one hospitalization of more than 48&#xD;
                  hours in past 90 days,&#xD;
&#xD;
               -  living in medical care house,&#xD;
&#xD;
               -  chronic hemodialysis,&#xD;
&#xD;
               -  home based wound care&#xD;
&#xD;
               -  resistant bacteria in the family environment&#xD;
&#xD;
          -  Morbidly obese subjects (BMI&gt;40 kg/m²)&#xD;
&#xD;
          -  Septic shock&#xD;
&#xD;
          -  Ceftaroline administered in past 14 days before inclusion&#xD;
&#xD;
          -  Diuretic treatment&#xD;
&#xD;
          -  Suspicion or confirmation pneumonia ceftaroline-resistant bacteria&#xD;
&#xD;
          -  Known hypersensitivity due to Ceftaroline or cephalosporin antibiotics&#xD;
&#xD;
          -  Known hypersensitivity due to Gentamicin or aminoglycosides antibiotics&#xD;
&#xD;
          -  Hypersensitivity due beta lactamin antibiotics&#xD;
&#xD;
          -  Anemia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CHU poitiers</name>
      <address>
        <city>Poitiers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <last_update_submitted>March 7, 2019</last_update_submitted>
  <last_update_submitted_qc>March 7, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 11, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ceftaroline fosamil</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/NCT03025841
org study id: CEFTAREA
nct id: NCT03025841
lead sponsor: 
Pneumonia is the most frequent infection in critically ill patients and remains a significant
      challenge to intensivists world-wide due to persisting high mortality and morbidity.
      Compelling evidence suggests that appropriate antibiotic therapy remains the most important
      intervention to improve patients' outcome, including the administration of a suitable
      molecule at an optimized dosage regimen. A vast array of pathophysiological changes can occur
      in critically ill patients that can complicate antibiotic dosing. Knowledge of the
      pharmacokinetic and pharmacodynamic properties of the antibiotics used for the management of
      critically ill patients is essential for selecting the antibiotic dosing regimens, which will
      optimize patient outcomes. Changes in volume of distribution (Vd) and clearance (CL) of
      antibiotics have been noted in these patients, which may affect the antibiotic concentration
      at the target site. It follows that the pharmacodynamic parameters that determine antibiotic
      efficacy, which can vary between antibiotic classes, may also be affected. Optimization of
      these parameters is necessary to maximize the rate of response through patient recovery and
      minimized antibiotic resistance.

      In a multicenter observational study in critically ill patients with normal plasma renal
      indices at admission, about 65% of patients manifested augmented creatinine clearance on at
      least one occasion in the first seven study days. Augmented creatinine clearance may
      significantly impact drug pharmacokinetics for a variety of renally eliminated
      pharmaceuticals (such as low-molecular weight heparins, aminoglycosides, glycopeptides, and
      β-lactams), leading to subtherapeutic concentrations and potentially adverse clinical
      outcomes. Currently little data exist that describe the consequences of augmented creatinine
      clearance on antibiotics PK.

      Ceftaroline (600 mg bid) is a cephalosporin with expanded gram-positive activity, including
      MRSA and penicillin-resistant streptococcus, which was approved by the US Food and Drug
      Administration (FDA) on October 29, 2010 for the treatment of acute bacterial SSSIs and
      community-acquired bacterial pneumonia. Ceftaroline showed also good activity against some of
      the common gram-negative respiratory pathogens (eg, Haemophilus influenzae, Moraxella
      catarrhalis, Neisseria meningitidis, and Pasteurella multocida). However, it does not display
      clinically relevant activity against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or
      Acinetobacter baumannii. Ceftaroline also lacks activity against gram-negative organisms with
      extended-spectrum β-lactamases. Importantly, because ceftaroline appears to induce AmpC
      β-lactamases despite MIC values in susceptible range, ittheoretically should be avoided in
      gram-negative bacteria known to harbor inducible AmpC β-lactamases (eg, Serratia, Proteus,
      Citrobacter, Morganella, Enterobacter, Providencia, and P. aeruginosa). In patients,
      ceftaroline is given as a prodrug, ceftaroline fosamil. After intravenous administration, the
      prodrug is rapidly transformed by plasma phosphatase enzymes to its bioactive metabolite. The
      pharmacokinetics of ceftaroline has been evaluated in single and multiple dose studies in
      healthy volunteers, in subjects with various degrees of renal impairment and in healthy
      elderly subjects. The volume of distribution is equal to 20.3 L, which corresponds to
      extracellular fluid volume. The protein binding is low (20%). The main route of elimination
      is via renal excretion, with a clearance estimated to160 mL/min close to the creatinine
      clearance. The elimination half-live is 2.6 h in adults with normal renal function.
      Unfortunately, no PK study has been performed in infected critically ill patients with
      augmented creatinine clearance. The best PK-PD index predicting drug efficacy is %Time>CMI. A
      bacteriostatic effect is achieved when free drug concentrations exceed the MIC for 30 to 40%
      of the dose administration interval (30 to 40%T>MIC). Near maximum organism kill is achieved
      at 50 to 60%T>MIC (30%T>MIC for Staphylococcus aureus).

      This project aims to characterize ceftaroline PK in patients with early-onset pneumonia and
      augmented creatinine clearance. The choice of ceftaroline is justified by its spectrum
      suitable for micro-organisms commonly encountered in early onset pneumonia, including
      methicillin-resistant Staphylococcus aureus. Secondary main objective is to predict the
      probably of reaching PK-PD targets using Monte Carlo simulations under various scenario in
      order to identify optimal ceftaroline administration schemes in critical care patients with
      various degrees of renal impairment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Minimum plasma concentration of Ceftaroline
time frame: Day 6
measure: Maximum plasma concentration of Ceftaroline
time frame: Day 6
measure: Volume of distribution of Ceftaroline in plasma
time frame: Day 6
measure: Clearance of Ceftaroline in plasma
time frame: Day 6
measure: Elimination half life of Ceftaroline in plasma
time frame: Day 6
measure: Pharmacokinetic measures outcomes to obtain the dosing regimens through the monte carlo simulation.
time frame: Day 6
description: in at least 90% of simulated subjects for minimal inhibitory concentration from 0.008 to 32 mg/L
measure: Clinical efficacy during Ceftaroline treatment and two weeks after end of it
time frame: Day 28
description: Patients will be considered to have clinical failure if they will have no response to the study drug on the basis of ongoing signs and symptoms of infection. Otherwise, patients will be considered to have clinical success
measure: Safety evaluation by adverse events and serious adverse events collection
time frame: One month following the last administration
arm group label: Ceftaroline
arm group type: Other
description: Patients receive Ceftaroline 600mg BID
intervention type: Drug
intervention name: Ceftaroline
arm group label: Ceftaroline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
facility: 
country: France
responsible party type: Sponsor
mesh term: Pneumonia
mesh term: Ceftaroline fosamil