" a Randomized Pilot Study of the Benefit of Nebulized Amikacin in the Treatment of Gram-negative Bacillus Pneumonia Acquired During Mechanical Ventilation in Patients Receiving Extracorporeal Membrane Veno-arterial Oxygenation (ECMO-VA)." (NAVAP-ECMO)

" a Randomized Pilot Study of the Benefit of Nebulized Amikacin in the Treatment of Gram-negative Bacillus Pneumonia Acquired During Mechanical Ventilation in Patients Receiving Extracorporeal Membrane Veno-arterial Oxygenation (ECMO-VA). "

Pneumonia are the most frequent infectious complication in patients on Extracorporeal Membrane Oxygenation Veno-arterial (ECMO-VA), with a treatment failure rate of around 40%, even though antibiotic therapy is tailored to the germs identified. One hypothesis to explain this particularly high failure rate is the reduced pulmonary blood flow associated with ECMO offloading of the heart. Although there are no data to date on the pulmonary penetration of antibiotics in patients undergoing VA-ECMO, this phenomenon of pulmonary hypoperfusion could contribute to altering the alveolocapillary diffusion of antibiotics, thereby reducing their concentration in the pulmonary parenchyma.

Our hypothesis is that amikacin nebulization could increase bacterial clearance and, ultimately, limit treatment failure or recurrence of gram-negative bacilli (GNB) pneumonia in patients undergoing VA-ECMO.

Study Overview

• Status: Not yet recruiting
• Conditions: Extracorporeal Membrane Oxygenation; Pneumonia, Bacterial
• Intervention / Treatment: Drug: Amikacin; Drug: Standard of care

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pauline DUREAU, MD, PhD; Phone Number: 01 84 82 76 89; Email: pauline.dureau@aphp.fr
• Study Contact Backup: Name: Alexis CALOC, Clinical project manager; Phone Number: 01 42 16 24 37; Email: alexis.caloc@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient 18 years or older
2. Circulatory assistance by veno-arterial ECMO for at least 24 hours prior to documentation of pneumonia
3. Invasive mechanical ventilation
4. Diagnostic suspicion of pneumonia based on evocative criteria (presence of at least 2 of the following criteria): fever (superior to 38. 5°C), hypothermia (inferior to 36.0°C), hyperleukocytosis (superior to 11 × 10^9 l-1) or leukopenia (inferior to 4 × 10^9 l-1), purulent tracheobronchial secretions, altered oxygenation with need to increase FiO2 on ECMO or ventilator for the same SaO2 or PaO2 target, new or persistent pulmonary infiltrate(s) on chest x-ray in bed, or image suggestive of pneumonia on chest CT, or consolidation of appearance suggestive of an infectious origin on pulmonary ultrasound.
5. And microbiological confirmation of Gram-negative ventilator-associated pneumonia by quantitative culture on bronchoalveolar lavage (BAL, significance threshold superior to 10^4 CFU/ml) or protected distal sampling (PDP, significance threshold superior to 10^3 CFU/ml).
6. Probabilistic antibiotic therapy with piperacillin - tazobactam
7. Informed consent obtained from the patient or trusted support person if unable to consent at the time of inclusion, or inclusion procedure in emergency situations.
8. Patient affiliated to social security (excluding AME)

Exclusion Criteria:

1. Known allergy to amikacin or another aminoglycoside or to an auxiliary drug or to any of their excipients.
2. Contraindication to the administration of amikacin or its excipients listed in the summary of product characteristics.
3. Contraindication to the administration of an auxiliary drug or to one of its excipients listed in the summary of product characteristics.
4. Contraindications to nebulization
5. Intravenous antibiotic therapy started more than 72 hours before randomization
6. Probabilistic venous antibiotic therapy other than piperacillin - tazobactam
7. Administration of inhaled antibiotics within 7 days prior to inclusion
8. Positive pregnancy test for women of childbearing potential
9. Presence of HIV infection with CD4 count inferior to 200 cells/mm3 or fungal lung infection or pulmonary abscess or empyema
10. Presence of renal insufficiency with creatinine clearance inferior to 15 ml/min, with the exception of patients receiving continuous renal purification or daily hemodialysis sessions as part of their intensive care unit management.
11. Patent moribund (SAPS II superior to 75) or high probability of death within 48 hours
12. Patient under legal protection (curatorship, guardianship or safeguard of justice)
13. Participating in another interventional clinical trial or within the exclusion period at the end of a previous study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care	Drug: Standard of care; Patients included in the standard of care group will not receive any nebulization. They will receive Standard care alone.
Experimental: Amikacine nebulization associated with Standard of care	Drug: Amikacin; Patients included in the inhaled amikacin group will receive inhaled antibiotic therapy by nebulization of amikacin at a dose of 25 mg/kg in 1 daily dose (+/- 3 hours apart), within 6 hours of randomization and for a total duration of 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bacterial eradication rate	Bacterial eradication rate, defined as absence of germs on direct examination and negative culture of a tracheal aspirate taken on day 5 (D5) after randomization and at least 12 hours after the last administration of inhaled amikacin.	Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure rate	Clinical cure rate, defined as disappearance of clinical signs suggestive of pneumonia, biological inflammatory syndrome and correction of haematosis disorders, at D5.	Day 5
Pneumonia persistence rate	Pneumonia persistence rate defined as the presence of the pathogen identified at a significant level on culture of tracheal aspirate at D5.	Day 5
Change in clinical pulmonary infection score (CPIS)	Difference between CPIS score at D5 and CPIS score at randomization.	Day 0 to Day 5
Change in pulmonary aeration score	Difference between ultrasound pulmonary aeration score at D5 and pulmonary aeration score at randomization.	Day 0 to Day 5
Adverse events	Quantifying and analysing adverse events and serious adverse events	Day 0 to Day 5
Pharmacokinetic analysis of piperacillin tazobactam	Pharmacokinetic analysis of plasma concentrations of the piperacillin - tazobactam combination	Day 1
Alveolar fluid penetration ratio of piperacillin-tazobactam	Measurement of the alveolar fluid penetration ratio (AUC* alveolar fluid / AUC plasma) of piperacillin-tazobactam in patients on ECMO-VA after 2 days of intravenous antibiotic administration. *Area Under the Curve	Day 1
Pharmacokinetic analysis of Amikacin	Measurement of the plasma concentration of Amikacin in patients on ECMO-VA in the treatment group between D1 and D5.	Day 1 to Day 5
Alveolar fluid concentration of Amikacin	Measurement of the alveolar fluid concentration of Amikacin in patients on ECMO-VA after one nebulization in the treatment group (after 24 hours of treatment)	Day 1

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): November 15, 2024
• Primary Completion (Estimated): May 15, 2025
• Study Completion (Estimated): May 15, 2026

Study Registration Dates

• First Submitted: September 17, 2024
• First Submitted That Met QC Criteria: September 17, 2024
• First Posted (Estimated): September 19, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 17, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: ECMO; Pharmacokinetic; Hospital acquired pneumonia; Antibiotic nebulization
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial; Anti-Infective Agents; Anti-Bacterial Agents; Amikacin
• Other Study ID Numbers: NAVAP-ECMO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No