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Nebulized Aztreonam for Prevention of Gram Negative Ventilator-associated Pneumonia (AZLIS)

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ClinicalTrials.gov Identifier: NCT03749226
Recruitment Status : Recruiting
First Posted : November 21, 2018
Last Update Posted : August 7, 2019
Sponsor:
Information provided by (Responsible Party):
Alejandro Rodriguez Oviedo , MD, Hospital Universitari Joan XXIII de Tarragona.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Ventilator Associated Pneumonia Prevention Respiratory Infection Other Drug: Aztreonam lysine Device: Aerogen Solo Device: CombiHaler Phase 2 Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
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

Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Efficacy, Safety and Pharmacokinetics Profile of Nebulized Aztreonam Lysine (AZLI) for Prevention of Gram Negative Pneumonia in Heavily Colonized Mechanically Ventilated Patients
Actual Study Start Date : March 19, 2019
Estimated Primary Completion Date : September 4, 2019
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
Active Comparator: AZLI 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
Drug: Aztreonam lysine
nebulization

Device: Aerogen Solo
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.

Device: CombiHaler
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.

No Intervention: Control group
Patients assigned to control group will no receive any intervention for heavy Gram negative colonization



Primary Outcome Measures :
  1. Microbiological cure [ Time Frame: 5 days ]
    Microbiological cure was defined as endotracheal aspirate (EA) or BAL cultures with consistently negative results after five day of therapy.


Secondary Outcome Measures :
  1. Pharmacokinetic of aztreonam lysine in respiratory samples [ Time Frame: day 0 and day 2 ]
    Maximum bronchial concentration[Cmax]

  2. Pharmacokinetic of aztreonam lysine in respiratory samples [ Time Frame: day 0 and day 2 ]
    time to maximum bronchial concentration[Tmax]

  3. Pharmacokinetic of aztreonam lysine in respiratory samples [ Time Frame: day 0 and day 2 ]
    Maximum bronchial concentration [Cmax] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples

  4. Pharmacokinetic of aztreonam lysine in respiratory samples [ Time Frame: day 0 and day 2 ]
    Area under the bronchial concentration-time curve [AUC] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples

  5. Pharmacokinetic of aztreonam lysine in respiratory samples [ Time Frame: day 0 and day 2 ]
    Terminal elimination half-time [t1/2] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples

  6. Pharmacokinetic profile of aztreonam lysine in serum samples [ Time Frame: day 3 ]
    Time to maximum serum concentration[Tmax] in serum samples

  7. Pharmacokinetic profile of aztreonam lysine in serum samples [ Time Frame: day 3 ]
    Area under the serum concentration-time curve [AUC] in serum samples

  8. Pharmacokinetic profile of aztreonam lysine in serum samples [ Time Frame: day 3 ]
    Terminal elimination half-time [t1/2] in serum samples

  9. SAEs and AEs assessments [ Time Frame: 10 days ]
    adverse events as assessed by CTCAE v5.0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Patients under mechanical ventilation for more than 5 day.
  3. Patient with heavy colonization by Gram‐negative microorganisms.
  4. No clinical suspicion of infections‐related ventilator‐associated complications (IVAC) according CDC criteria (Figure 1).
  5. Patients or his/her legal representative with ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments.
  6. Informed consent signed

Exclusion Criteria:

  1. Suspected of IVAC.
  2. Patients with known hypersensitivity to Aztreonam.
  3. Patients who received more than 48 hours of broad spectrum antibiotics.
  4. Evidence of active mycobacterium infections, chronic pulmonary infection or bronchial obstruction.
  5. Granulomatous disease, lung cancer or lung transplant.
  6. Acute respiratory distress syndrome (ARDS)
  7. Woman who is pregnant or breast‐feeding while enrolled in this study.
  8. Any medical condition which, in the opinion of the Investigator, places the patient at an unacceptable risk for toxicities if entered into the clinical study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03749226


Contacts
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Contact: Alejandro H Rodriguez Oviedo, MD,PhD +34977295818 ahr1161@yahoo.es
Contact: Sandra I Trefler Crespo, BsC,PhD +34977295818 sitrefler@yahoo.es

Locations
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Spain
Critical Care Department - Hospital Universitario de Tarragona Joan XXIII Recruiting
Tarragona, Spain, 43007
Contact: Alejandro Rodriguez Oviedo    977295818    ahr1161@yahoo.es   
Sponsors and Collaborators
Hospital Universitari Joan XXIII de Tarragona.
Publications of Results:
Other Publications:

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Responsible Party: Alejandro Rodriguez Oviedo , MD, Principal Investigator, Hospital Universitari Joan XXIII de Tarragona.
ClinicalTrials.gov Identifier: NCT03749226    
Other Study ID Numbers: AZLI-2018-AR
First Posted: November 21, 2018    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alejandro Rodriguez Oviedo , MD, Hospital Universitari Joan XXIII de Tarragona.:
Nebulized antibiotic
Ventilator associated pneumonia
Ventilated associated tracheobronchitis
Aztreonam lysine
Additional relevant MeSH terms:
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Pneumonia, Ventilator-Associated
Respiratory Tract Infections
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Cross Infection
Infection
Aztreonam
Anti-Bacterial Agents
Anti-Infective Agents