<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/NCT03790176</url>
  </required_header>
  <id_info>
    <org_study_id>Version 2.2 April 19, 2018</org_study_id>
    <nct_id>NCT03790176</nct_id>
  </id_info>
  <brief_title>ZAVI APD ELF Protocol v2.2</brief_title>
  <official_title>Plasma, ELF and Intraperitoneal Pharmacokinetics of Ceftazidime/Avibactam in Critically Ill and Peritoneal Dialysis Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Markus Zeitlinger</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Vienna</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      CAZ/AVI is a new antibiotic drug that is meant to be used for various indications including&#xD;
      cIAI and nosocomial pneumonia. To date, limited data exists on PK of CAZ/AVI in patients&#xD;
      undergoing peritoneal dialysis as well as on penetration of CAZ/AVI in ELF of critically ill&#xD;
      patients. The present study is carried out to determine target site PK of CAZ/AVI in these&#xD;
      two populations, in order to contribute to a more complete understanding of the drug's&#xD;
      penetration to its site of action.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ceftazidime/Avibactam (CAZ/AVI) is a novel antibiotic drug that has recently become&#xD;
      available. It consists of a β-lactam/β-lactamase fixed drug combination with an almost&#xD;
      exclusively Gram-negative spectrum and is indicated for the treatment of:&#xD;
&#xD;
        -  complicated intra-abdominal infections (cIAI)&#xD;
&#xD;
        -  complicated urinary tract infection (cUTI), including pyelonephritis&#xD;
&#xD;
        -  hospital-acquired pneumonia including ventilator-associated pneumonia (VAP)&#xD;
&#xD;
        -  infections due to aerobic Gram-negative organisms in patients with limited treatment&#xD;
           options.&#xD;
&#xD;
      It is common knowledge that in anti-infective therapy, sufficient drug delivery to the target&#xD;
      site is essential for antimicrobial efficacy and prevention of bacterial resistance. Based on&#xD;
      this premise, the present exploratory trial will focus on the pharmacokinetics (PK) of&#xD;
      CAZ/AVI in two patient populations:&#xD;
&#xD;
      PART A will investigate PK of CAZ/AVI in plasma and peritoneal dialysis fluid of patients&#xD;
      undergoing automated peritoneal dialysis (APD). After a single intravenous dose of the drug&#xD;
      PK sampling of CAZ/AVI will be performed in plasma and in peritoneal dialysis fluid,&#xD;
      respectively. On the one hand, this will help to assess intraperitoneal exposure to CAZ/AVI&#xD;
      after intravenous administration. This information might be of crucial importance for&#xD;
      patients with infections localized in the peritoneal space. On the other hand, this study&#xD;
      will show whether and to which extent CAZ/AVI is cleared from the bloodstream after&#xD;
      intravenous administration in patients undergoing APD and receiving CAZ/AVI as treatment of&#xD;
      other systemic infections, e.g. nosocomial pneumonia. Both aspects will improve current&#xD;
      information on CAZ/AVI PK in peritoneal dialysis.&#xD;
&#xD;
      PART B will determine steady-state plasma and epithelial lining fluid (ELF) concentrations of&#xD;
      CAZ/AVI in critically ill patients receiving the drug for treatment of nosocomial pneumonia&#xD;
      (including VAP) at the discretion of their treating physicians. Penetration of CAZ/AVI into&#xD;
      ELF has already been assessed in healthy volunteers and amounted roughly to 30% of plasma&#xD;
      exposure. However, several physiological factors determining the amount of drug eventually&#xD;
      recovered in ELF might be altered in critical illness (hemodynamics, binding to plasma and/or&#xD;
      tissue proteins, local inflammation processes etc). Thus, PK of CAZ/AVI in lungs of&#xD;
      critically ill patients might significantly differ from healthy volunteers, and deriving ELF&#xD;
      exposure solely from plasma pharmacokinetics might not be entirely reliable in this&#xD;
      circumstance. Still, considering the premise mentioned above, this issue is of crucial&#xD;
      importance. The present study will help to assess whether CAZ/AVI reaches its target site&#xD;
      (for the indication of nosocomial pneumonia) in critically ill patients to a sufficient&#xD;
      degree.&#xD;
&#xD;
      Taken together, the information retrieved by this study will contribute to a better&#xD;
      understanding of CAZ/AVI's disposition in target compartments of two patient populations and&#xD;
      corroborate (or challenge) current dosing recommendations.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 1, 2018</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">December 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>group A - patients on automated peritoneal dialysis group B - critically ill patients with pneumonia</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the concentration time curve (AUC) from 0 to 8 hours (AUC0-8)</measure>
    <time_frame>on study days</time_frame>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Peritonitis</condition>
  <condition>Pneumonia</condition>
  <arm_group>
    <arm_group_label>A - patients on automated peritoneal dialysis</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>each of n=8 patients will receive one single intravenous infusion of ceftazidime/avibactam (CAZ/AVI) 2g/0.5g over two hours. Subsequently, PK of CAZ/AVI will be determined in plasma and peritoneal dialysis fluid (and urine, if applicable) at protocol-defined time points over 24 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B - critically ill patients with pneumonia</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>following one intravenous dose of 2g/0.5g CAZ/AVI (which patients will receive based on clinical indication by their treating physician), PK of CAZ/AVI will be determined at protocol-defined time points over one dosing interval in plasma and in epithelial lining fluid (ELF).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravenous Infusion</intervention_name>
    <description>see arm/group description. NO INTERVENTION IN STUDY GROUP B! PATIENTS OF GROUP B WILL RECEIVE CAZ/AVI INDEPENDENTLY FROM STUDY PARTICIPATION BASED ON DECISION OF THEIR TREATING PHYSICIAN</description>
    <arm_group_label>A - patients on automated peritoneal dialysis</arm_group_label>
    <arm_group_label>B - critically ill patients with pneumonia</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria (PART A - PATIENTS UNDERGOING APD):&#xD;
&#xD;
          -  Males or females aged between 18 and 85 years undergoing automated peritoneal dialysis&#xD;
             (APD)&#xD;
&#xD;
          -  Written informed consent given after being provided detailed information about the&#xD;
             nature, risks, and scope of the clinical study as well as the expected desirable and&#xD;
             adverse effects of the drug&#xD;
&#xD;
          -  No legal incapacity and/or other circumstances rendering the subject unable to&#xD;
             understand the nature, scope and possible consequences of the study&#xD;
&#xD;
        Exclusion criteria (PART A - PATIENTS UNDERGOING APD):&#xD;
&#xD;
          -  Known allergy or hypersensitivity against study drug or other beta-lactam antibiotics&#xD;
&#xD;
          -  History of severe allergic or anaphylactic reactions to any medication&#xD;
&#xD;
          -  Any systemic infection&#xD;
&#xD;
          -  Peritonitis or catheter-related infection which required antibiotic treatment within 2&#xD;
             months prior to the start of the study&#xD;
&#xD;
          -  Pregancy or, in case of women of child-bearing potential, lack of willingness to apply&#xD;
             adequate contraception measures during study period&#xD;
&#xD;
          -  Haemoglobin below 9 g/dl&#xD;
&#xD;
          -  Other objections to participate in the study in the opinion of the investigator&#xD;
&#xD;
        Inclusion criteria (PART B - CRITICALLY ILL PATIENTS):&#xD;
&#xD;
          -  Age above 18 years&#xD;
&#xD;
          -  Intubated patients admitted to an intensive care unit of the Vienna general hospital&#xD;
             (AKH) participating in this study&#xD;
&#xD;
          -  Sequential organ failure assessment (SOFA) score &gt; 6 at study inclusion&#xD;
&#xD;
          -  Clinical diagnosis of nosocomial pneumonia or VAP&#xD;
&#xD;
          -  Body mass index (calculated from measured or estimated body weight and height) between&#xD;
             18 and 40&#xD;
&#xD;
          -  Therapy with CAZ/AVI at a dosage of 2g/0.5g three times daily (indication at the&#xD;
             discretion of the treating physicians)&#xD;
&#xD;
        Exclusion criteria (PART B - CRITICALLY ILL PATIENTS):&#xD;
&#xD;
          -  Known allergy or hypersensitivity against study drug or other beta-lactam antibiotics&#xD;
&#xD;
          -  Any disease considered relevant for proper performance of the study, or risks to the&#xD;
             patient, at the discretion of the investigator&#xD;
&#xD;
          -  Impaired renal function denoted by an estimated GFR of &lt;50 mL/min according to&#xD;
             Cockroft-Gault at study inclusion&#xD;
&#xD;
          -  Requiring hemofiltration or hemodialysis&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Other factors that preclude study participation in the opinion of the investigator&#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>Medical University of Vienna</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Markus Zeitlinger, MD</last_name>
      <phone>0043140400</phone>
      <phone_ext>29810</phone_ext>
      <email>klin-pharmakologie@meduniwien.ac.at</email>
    </contact>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 27, 2018</study_first_submitted>
  <study_first_submitted_qc>December 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 31, 2018</study_first_posted>
  <last_update_submitted>August 31, 2021</last_update_submitted>
  <last_update_submitted_qc>August 31, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Markus Zeitlinger</investigator_full_name>
    <investigator_title>Assoc. Prof. Priv. Doz. Dr.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peritonitis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03790176
org study id: Version 2.2 April 19, 2018
nct id: NCT03790176
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
CAZ/AVI is a new antibiotic drug that is meant to be used for various indications including
      cIAI and nosocomial pneumonia. To date, limited data exists on PK of CAZ/AVI in patients
      undergoing peritoneal dialysis as well as on penetration of CAZ/AVI in ELF of critically ill
      patients. The present study is carried out to determine target site PK of CAZ/AVI in these
      two populations, in order to contribute to a more complete understanding of the drug's
      penetration to its site of action.
Ceftazidime/Avibactam (CAZ/AVI) is a novel antibiotic drug that has recently become
      available. It consists of a β-lactam/β-lactamase fixed drug combination with an almost
      exclusively Gram-negative spectrum and is indicated for the treatment of:

        -  complicated intra-abdominal infections (cIAI)

        -  complicated urinary tract infection (cUTI), including pyelonephritis

        -  hospital-acquired pneumonia including ventilator-associated pneumonia (VAP)

        -  infections due to aerobic Gram-negative organisms in patients with limited treatment
           options.

      It is common knowledge that in anti-infective therapy, sufficient drug delivery to the target
      site is essential for antimicrobial efficacy and prevention of bacterial resistance. Based on
      this premise, the present exploratory trial will focus on the pharmacokinetics (PK) of
      CAZ/AVI in two patient populations:

      PART A will investigate PK of CAZ/AVI in plasma and peritoneal dialysis fluid of patients
      undergoing automated peritoneal dialysis (APD). After a single intravenous dose of the drug
      PK sampling of CAZ/AVI will be performed in plasma and in peritoneal dialysis fluid,
      respectively. On the one hand, this will help to assess intraperitoneal exposure to CAZ/AVI
      after intravenous administration. This information might be of crucial importance for
      patients with infections localized in the peritoneal space. On the other hand, this study
      will show whether and to which extent CAZ/AVI is cleared from the bloodstream after
      intravenous administration in patients undergoing APD and receiving CAZ/AVI as treatment of
      other systemic infections, e.g. nosocomial pneumonia. Both aspects will improve current
      information on CAZ/AVI PK in peritoneal dialysis.

      PART B will determine steady-state plasma and epithelial lining fluid (ELF) concentrations of
      CAZ/AVI in critically ill patients receiving the drug for treatment of nosocomial pneumonia
      (including VAP) at the discretion of their treating physicians. Penetration of CAZ/AVI into
      ELF has already been assessed in healthy volunteers and amounted roughly to 30% of plasma
      exposure. However, several physiological factors determining the amount of drug eventually
      recovered in ELF might be altered in critical illness (hemodynamics, binding to plasma and/or
      tissue proteins, local inflammation processes etc). Thus, PK of CAZ/AVI in lungs of
      critically ill patients might significantly differ from healthy volunteers, and deriving ELF
      exposure solely from plasma pharmacokinetics might not be entirely reliable in this
      circumstance. Still, considering the premise mentioned above, this issue is of crucial
      importance. The present study will help to assess whether CAZ/AVI reaches its target site
      (for the indication of nosocomial pneumonia) in critically ill patients to a sufficient
      degree.

      Taken together, the information retrieved by this study will contribute to a better
      understanding of CAZ/AVI's disposition in target compartments of two patient populations and
      corroborate (or challenge) current dosing recommendations.
allocation: Non-Randomized
intervention model: Single Group Assignment
intervention model description: group A - patients on automated peritoneal dialysis group B - critically ill patients with pneumonia
primary purpose: Other
masking: None (Open Label)
measure: Area under the concentration time curve (AUC) from 0 to 8 hours (AUC0-8)
time frame: on study days
arm group label: A - patients on automated peritoneal dialysis
arm group type: Other
description: each of n=8 patients will receive one single intravenous infusion of ceftazidime/avibactam (CAZ/AVI) 2g/0.5g over two hours. Subsequently, PK of CAZ/AVI will be determined in plasma and peritoneal dialysis fluid (and urine, if applicable) at protocol-defined time points over 24 hours.
arm group label: B - critically ill patients with pneumonia
arm group type: Other
description: following one intravenous dose of 2g/0.5g CAZ/AVI (which patients will receive based on clinical indication by their treating physician), PK of CAZ/AVI will be determined at protocol-defined time points over one dosing interval in plasma and in epithelial lining fluid (ELF).
intervention type: Drug
intervention name: Intravenous Infusion
description: see arm/group description. NO INTERVENTION IN STUDY GROUP B! PATIENTS OF GROUP B WILL RECEIVE CAZ/AVI INDEPENDENTLY FROM STUDY PARTICIPATION BASED ON DECISION OF THEIR TREATING PHYSICIAN
arm group label: A - patients on automated peritoneal dialysis
arm group label: B - critically ill patients with pneumonia
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
country: Austria
responsible party type: Sponsor-Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Markus Zeitlinger
investigator title: Assoc. Prof. Priv. Doz. Dr.
mesh term: Peritonitis
sharing ipd: No