<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/NCT03749226</url>
  </required_header>
  <id_info>
    <org_study_id>AZLI-2018-AR</org_study_id>
    <nct_id>NCT03749226</nct_id>
  </id_info>
  <brief_title>Nebulized Aztreonam for Prevention of Gram Negative Ventilator-associated Pneumonia</brief_title>
  <acronym>AZLIS</acronym>
  <official_title>Efficacy, Safety and Pharmacokinetics Profile of Nebulized Aztreonam Lysine (AZLI) for Prevention of Gram Negative Pneumonia in Heavily Colonized Mechanically Ventilated Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Universitari Joan XXIII de Tarragona.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital Universitari Joan XXIII de Tarragona.</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>
      Aerosol antibiotic administration offers the theoretical advantages of achieving high drug&#xD;
      concentration at the infection site and low systemic absorption, thereby avoiding toxicity.&#xD;
      Antibiotic aerosolization has good results in patients with cystic fibrosis, but data are&#xD;
      scarce for patients under mechanical ventilation.&#xD;
&#xD;
      Prospective, randomized 1:1, open-label study to assess the microbiological cure and&#xD;
      pharmacokinetics (PK), safety and efficacy of nebulized Aztreonam lysine (75 mg dose) each 8&#xD;
      hr during 5 days in ventilated patients heavily colonized by Gram-negative bacteria. It is&#xD;
      planned to include a total of 20 ventilated patients heavily colonized. Only ten of them&#xD;
      (active group) will receive 5 days of treatment with nebulized AZLI.The control group will&#xD;
      not receive treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main objectives of this study is:&#xD;
&#xD;
      To compare the microbiological cure at day 5 of treatment and the incidence of Gram-negative&#xD;
      IVAC between 7th and 10th days after last dose in patients heavily colonized by Gram-negative&#xD;
      bacteria treated with nebulized AZLI vs. no treatment.&#xD;
&#xD;
      The secundary objective of this study are:&#xD;
&#xD;
        1. Safety and tolerability of AZLI administered during 5 days in adults patients under&#xD;
           mechanical ventilation heavily colonized by Gram-negative bacteria&#xD;
&#xD;
        2. The pharmacokinetic profile in endotracheal aspirate (EA) or bronchoalveolar lavage&#xD;
           (BAL).&#xD;
&#xD;
        3. The plasma levels of nebulized AZLI in patients under mechanical ventilation heavily&#xD;
           colonized by Gram-negative bacteria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    due to COVID-19 pandemia&#xD;
  </why_stopped>
  <start_date type="Actual">March 19, 2019</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">September 4, 2019</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Twenty consecutive patients heavily colonized by Gram-negative bacteria will be eligible for this study. Patients will be randomized to receive either AZLI nebulized or nothing via 1:1 randomization at study or control group.&#xD;
Patients assigned to study group will receive nebulized Aztreonam lysine (AZLI 75 mg-dose) three times /day during 5 days by mean of the ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer adapted of the ventilator. All patients will be on conventional volume-control ventilator setting during the antibiotic therapy. Systemic antibiotics will not be used in any patient. If the attending physician saw the need to administer intravenous antibiotics after the patient has entry in the study, this patients should be removed from the study</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Microbiological cure</measure>
    <time_frame>5 days</time_frame>
    <description>Microbiological cure was defined as endotracheal aspirate (EA) or BAL cultures with consistently negative results after five day of therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic of aztreonam lysine in respiratory samples</measure>
    <time_frame>day 0 and day 2</time_frame>
    <description>Maximum bronchial concentration[Cmax]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic of aztreonam lysine in respiratory samples</measure>
    <time_frame>day 0 and day 2</time_frame>
    <description>time to maximum bronchial concentration[Tmax]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic of aztreonam lysine in respiratory samples</measure>
    <time_frame>day 0 and day 2</time_frame>
    <description>Maximum bronchial concentration [Cmax] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic of aztreonam lysine in respiratory samples</measure>
    <time_frame>day 0 and day 2</time_frame>
    <description>Area under the bronchial concentration-time curve [AUC] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic of aztreonam lysine in respiratory samples</measure>
    <time_frame>day 0 and day 2</time_frame>
    <description>Terminal elimination half-time [t1/2] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of aztreonam lysine in serum samples</measure>
    <time_frame>day 3</time_frame>
    <description>Time to maximum serum concentration[Tmax] in serum samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of aztreonam lysine in serum samples</measure>
    <time_frame>day 3</time_frame>
    <description>Area under the serum concentration-time curve [AUC] in serum samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of aztreonam lysine in serum samples</measure>
    <time_frame>day 3</time_frame>
    <description>Terminal elimination half-time [t1/2] in serum samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SAEs and AEs assessments</measure>
    <time_frame>10 days</time_frame>
    <description>adverse events as assessed by CTCAE v5.0</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Ventilator Associated Pneumonia</condition>
  <condition>Prevention</condition>
  <condition>Respiratory Infection Other</condition>
  <arm_group>
    <arm_group_label>AZLI group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients assigned to study group will receive nebulized Aztreonam lysine (AZLI 75 mg-dose) three times /day during 5 days by mean of the ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer adapted of the ventilator</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients assigned to control group will no receive any intervention for heavy Gram negative colonization</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aztreonam lysine</intervention_name>
    <description>nebulization</description>
    <arm_group_label>AZLI group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Aerogen Solo</intervention_name>
    <description>Aerogen's vibrating mesh technology, available within the Aerogen® Solo has been adopted for use of conventional mechanical ventilation. Aerogen Solo utilizes active vibrating mesh technology, where energy applied to the vibrational element, causes vibration of each of the 1000 funnel shaped apertures within the mesh. The mesh acts as a micropump drawing liquid through the holes producing a low velocity aerosol optimized for targeted drug delivery to the lungs. According our study (Rodriguez A et al , Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453) Aeroneb Solo showed an excellent aerosol delivery profile for Aztreonam lysine (AZLI) in an in vitro model of MV with short drug delivery time.</description>
    <arm_group_label>AZLI group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>CombiHaler</intervention_name>
    <description>The inhalation chamber CombiHaler™ spacer for mechanical ventilation and critical care (ICU) allows using both a vibrating mesh nebulizer such as Aeroneb ™, and a pMDI. It saves 50% of the nebulized drug when used in invasive ventilation. The inhalation chamber CombiHaler® is integrated on a circuit of a breathing device in invasive ventilation in particular for connexion of an Aeroneb® Pro or an Aeroneb® Solo. According our study (Rodriguez A et al , Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453) a better aerosol delivery performance (30%) was obtained using the Conbihaler spacer.</description>
    <arm_group_label>AZLI group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years.&#xD;
&#xD;
          2. Patients under mechanical ventilation for more than 5 day.&#xD;
&#xD;
          3. Patient with heavy colonization by Gram-negative microorganisms.&#xD;
&#xD;
          4. No clinical suspicion of infections-related ventilator-associated complications (IVAC)&#xD;
             according CDC criteria (Figure 1).&#xD;
&#xD;
          5. Patients or his/her legal representative with ability to understand the requirements&#xD;
             of the study, provide written informed consent and authorization of use and disclosure&#xD;
             of protected health information, and agree to abide by the study restrictions and to&#xD;
             return for the required assessments.&#xD;
&#xD;
          6. Informed consent signed&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Suspected of IVAC.&#xD;
&#xD;
          2. Patients with known hypersensitivity to Aztreonam.&#xD;
&#xD;
          3. Patients who received more than 48 hours of broad spectrum antibiotics.&#xD;
&#xD;
          4. Evidence of active mycobacterium infections, chronic pulmonary infection or bronchial&#xD;
             obstruction.&#xD;
&#xD;
          5. Granulomatous disease, lung cancer or lung transplant.&#xD;
&#xD;
          6. Acute respiratory distress syndrome (ARDS)&#xD;
&#xD;
          7. Woman who is pregnant or breast-feeding while enrolled in this study.&#xD;
&#xD;
          8. Any medical condition which, in the opinion of the Investigator, places the patient at&#xD;
             an unacceptable risk for toxicities if entered into the clinical study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Critical Care Department - Hospital Universitario de Tarragona Joan XXIII</name>
      <address>
        <city>Tarragona</city>
        <zip>43007</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
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  <results_reference>
    <citation>Rodriguez A, Cabrera M, Reyes LF, Bodi M, Trefler S, Canadell L, Barahona D, Ehrmann S, Martin-Loeches I, Restrepo MI, Vecellio L. In vitro evaluation of aerosol delivery of aztreonam lysine (AZLI): an adult mechanical ventilation model. Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453. doi: 10.1080/17425247.2017.1393411. Epub 2017 Oct 23.</citation>
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  <verification_date>June 2021</verification_date>
  <study_first_submitted>April 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>June 29, 2021</last_update_submitted>
  <last_update_submitted_qc>June 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital Universitari Joan XXIII de Tarragona.</investigator_affiliation>
    <investigator_full_name>Alejandro Rodriguez Oviedo , MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Nebulized antibiotic</keyword>
  <keyword>Ventilator associated pneumonia</keyword>
  <keyword>Ventilated associated tracheobronchitis</keyword>
  <keyword>Aztreonam lysine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Respiratory Tract Infections</mesh_term>
    <mesh_term>Pneumonia, Ventilator-Associated</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aztreonam</mesh_term>
  </intervention_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/NCT03749226
org study id: AZLI-2018-AR
nct id: NCT03749226
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Aerosol antibiotic administration offers the theoretical advantages of achieving high drug
      concentration at the infection site and low systemic absorption, thereby avoiding toxicity.
      Antibiotic aerosolization has good results in patients with cystic fibrosis, but data are
      scarce for patients under mechanical ventilation.

      Prospective, randomized 1:1, open-label study to assess the microbiological cure and
      pharmacokinetics (PK), safety and efficacy of nebulized Aztreonam lysine (75 mg dose) each 8
      hr during 5 days in ventilated patients heavily colonized by Gram-negative bacteria. It is
      planned to include a total of 20 ventilated patients heavily colonized. Only ten of them
      (active group) will receive 5 days of treatment with nebulized AZLI.The control group will
      not receive treatment.
The main objectives of this study is:

      To compare the microbiological cure at day 5 of treatment and the incidence of Gram-negative
      IVAC between 7th and 10th days after last dose in patients heavily colonized by Gram-negative
      bacteria treated with nebulized AZLI vs. no treatment.

      The secundary objective of this study are:

        1. Safety and tolerability of AZLI administered during 5 days in adults patients under
           mechanical ventilation heavily colonized by Gram-negative bacteria

        2. The pharmacokinetic profile in endotracheal aspirate (EA) or bronchoalveolar lavage
           (BAL).

        3. The plasma levels of nebulized AZLI in patients under mechanical ventilation heavily
           colonized by Gram-negative bacteria.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Twenty consecutive patients heavily colonized by Gram-negative bacteria will be eligible for this study. Patients will be randomized to receive either AZLI nebulized or nothing via 1:1 randomization at study or control group.
Patients assigned to study group will receive nebulized Aztreonam lysine (AZLI 75 mg-dose) three times /day during 5 days by mean of the ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer adapted of the ventilator. All patients will be on conventional volume-control ventilator setting during the antibiotic therapy. Systemic antibiotics will not be used in any patient. If the attending physician saw the need to administer intravenous antibiotics after the patient has entry in the study, this patients should be removed from the study
primary purpose: Prevention
masking: None (Open Label)
measure: Microbiological cure
time frame: 5 days
description: Microbiological cure was defined as endotracheal aspirate (EA) or BAL cultures with consistently negative results after five day of therapy.
measure: Pharmacokinetic of aztreonam lysine in respiratory samples
time frame: day 0 and day 2
description: Maximum bronchial concentration[Cmax]
measure: Pharmacokinetic of aztreonam lysine in respiratory samples
time frame: day 0 and day 2
description: time to maximum bronchial concentration[Tmax]
measure: Pharmacokinetic of aztreonam lysine in respiratory samples
time frame: day 0 and day 2
description: Maximum bronchial concentration [Cmax] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples
measure: Pharmacokinetic of aztreonam lysine in respiratory samples
time frame: day 0 and day 2
description: Area under the bronchial concentration-time curve [AUC] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples
measure: Pharmacokinetic of aztreonam lysine in respiratory samples
time frame: day 0 and day 2
description: Terminal elimination half-time [t1/2] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples
measure: Pharmacokinetic profile of aztreonam lysine in serum samples
time frame: day 3
description: Time to maximum serum concentration[Tmax] in serum samples
measure: Pharmacokinetic profile of aztreonam lysine in serum samples
time frame: day 3
description: Area under the serum concentration-time curve [AUC] in serum samples
measure: Pharmacokinetic profile of aztreonam lysine in serum samples
time frame: day 3
description: Terminal elimination half-time [t1/2] in serum samples
measure: SAEs and AEs assessments
time frame: 10 days
description: adverse events as assessed by CTCAE v5.0
arm group label: AZLI group
arm group type: Active Comparator
description: Patients assigned to study group will receive nebulized Aztreonam lysine (AZLI 75 mg-dose) three times /day during 5 days by mean of the ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer adapted of the ventilator
arm group label: Control group
arm group type: No Intervention
description: Patients assigned to control group will no receive any intervention for heavy Gram negative colonization
intervention type: Drug
intervention name: Aztreonam lysine
description: nebulization
arm group label: AZLI group
intervention type: Device
intervention name: Aerogen Solo
description: Aerogen's vibrating mesh technology, available within the Aerogen® Solo has been adopted for use of conventional mechanical ventilation. Aerogen Solo utilizes active vibrating mesh technology, where energy applied to the vibrational element, causes vibration of each of the 1000 funnel shaped apertures within the mesh. The mesh acts as a micropump drawing liquid through the holes producing a low velocity aerosol optimized for targeted drug delivery to the lungs. According our study (Rodriguez A et al , Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453) Aeroneb Solo showed an excellent aerosol delivery profile for Aztreonam lysine (AZLI) in an in vitro model of MV with short drug delivery time.
arm group label: AZLI group
intervention type: Device
intervention name: CombiHaler
description: The inhalation chamber CombiHaler™ spacer for mechanical ventilation and critical care (ICU) allows using both a vibrating mesh nebulizer such as Aeroneb ™, and a pMDI. It saves 50% of the nebulized drug when used in invasive ventilation. The inhalation chamber CombiHaler® is integrated on a circuit of a breathing device in invasive ventilation in particular for connexion of an Aeroneb® Pro or an Aeroneb® Solo. According our study (Rodriguez A et al , Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453) a better aerosol delivery performance (30%) was obtained using the Conbihaler spacer.
arm group label: AZLI group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Spain
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responsible party type: Principal Investigator
investigator affiliation: Hospital Universitari Joan XXIII de Tarragona.
investigator full name: Alejandro Rodriguez Oviedo , MD
investigator title: Principal Investigator
mesh term: Pneumonia
mesh term: Respiratory Tract Infections
mesh term: Pneumonia, Ventilator-Associated
mesh term: Aztreonam
sharing ipd: No