Evaluation of Nebulized Amikacin Sulfate in Combination with Piperacillin Sodium and Tazobactam Sodium for Gram-Negative Pneumonia in VA-ECMO Patients

The primary objective of this study is to evaluate whether the administration of **inhaled amikacin** for 5 days, in conjunction with standard antibiotic therapy, enhances the bacterial eradication rate at day 5 in adult patients with documented **gram-negative bacillus pneumonia** undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO), compared to standard antibiotic therapy alone. This is clinically relevant as it may offer an improved therapeutic strategy for managing pneumonia in this critically ill patient population.

Secondary objectives include:

• Comparing the clinical cure rate at day 5 between the inhaled amikacin group with standard antibiotic therapy and the standard antibiotic therapy group alone.
• Comparing the rate of persistence of pneumonia at day 5 between the two groups.
• Assessing the evolution of the clinical pulmonary infection score (CPIS) from randomization to day 5 between the two groups.
• Evaluating the evolution of the lung aeration assessment score via lung ultrasound from randomization to day 5 between the two groups.
• Comparing adverse events and serious adverse events between the two groups.
• Measuring plasma and alveolar concentrations of **piperacillin-tazobactam** at equilibrium after 2 days of treatment in patients undergoing VA-ECMO.

The clinical trial involves adult participants diagnosed with **gram-negative bacillus pneumonia** acquired during mechanical ventilation while receiving Extracorporeal Membrane veno-arterial oxygenation (VA-ECMO). The study population includes both male and female subjects aged 18 years and older. Participants are selected based on specific criteria, including the requirement for circulatory assistance by VA-ECMO for at least 24 hours prior to pneumonia documentation and the presence of invasive mechanical ventilation. The trial population is characterized by a vulnerable status, as indicated by the inclusion of individuals who may be unable to provide informed consent independently. The sponsor has not provided the total number of participants involved in the study. Lifestyle factors such as diet and physical activity are not specified in the available data. Key inclusion criteria include microbiological confirmation of gram-negative ventilator-associated pneumonia and the administration of probabilistic antibiotic therapy with piperacillin-tazobactam. Participants must be affiliated with a social security scheme, excluding AME, and informed consent must be obtained from the patient or a trusted support person.

The clinical trial is designed to evaluate the efficacy of **amikacin sulfate** administered via nebulization in patients with gram-negative bacillus pneumonia acquired during mechanical ventilation while receiving Extracorporeal Membrane veno-arterial oxygenation (VA-ECMO). This is a randomized, controlled, double-blind study with a primary objective to assess the bacterial eradication rate at day 5 (D5) following the administration of inhaled amikacin in addition to standard antibiotic therapy. The trial is set to commence on June 15, 2024, and is expected to conclude by December 22, 2025.

Participants will be randomly assigned to receive either the investigational treatment or the standard therapy. The study will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as age ≥ 18 years, ECMO support for at least 24 hours, and microbiological confirmation of pneumonia. Follow-up visits will occur throughout the treatment period, with a critical assessment on D5 to evaluate the primary endpoint of bacterial eradication. The end-of-study visit will finalize data collection and assess secondary endpoints, including clinical cure rate and adverse events.

The expected duration of participant involvement is approximately 5 days, aligning with the maximum treatment period for the investigational product. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any clinical decision by the investigator deeming it necessary for the participant's safety. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the results, contributing valuable insights into the management of pneumonia in this critically ill population.

The clinical trial involves the administration of **Piperacillin Sodium** and **Tazobactam Sodium** as part of the experimental treatment. This combination is provided in the form of an intravenous infusion, classified under the ATC code J01CR05, which denotes its role as a **beta-lactamase inhibitor**. The pharmaceutical form is identified as PHF00230MIG. The maximum daily dose is 18 grams, with a total maximum dose of 72 grams over a treatment period of up to 4 days. The administration is conducted intravenously, and the treatment is not formulated for pediatric use. Participant compliance is monitored through standard clinical trial procedures to ensure adherence to the dosing schedule.

In addition to the experimental treatment, **Amikacin Sulfate** is utilized as a non-experimental treatment in the study. This antibiotic is administered via nasal use, facilitated by a nebulization device, specifically the Aerogen® Solo, which is CE marked. The pharmaceutical form is PHF00231MIG, and the ATC code is J01GB06. The dosing regimen involves a maximum daily dose of 25 mg/kg, with a total maximum dose of 125 mg/kg over a 5-day treatment period. The nebulization process ensures targeted delivery to the lungs, optimizing the therapeutic effect. Compliance with the dosing schedule is monitored to ensure accurate administration and efficacy of the treatment.

Efficacy in the clinical trial titled "Nebulized Amikacine for Ventilator associated gram negative Pneumonia in ECMO veno-arterial patients: A randomized Pilot Study (NAVAP-ECMO)" will be assessed using both primary and secondary endpoints. The primary endpoint is the **bacterial eradication rate**, defined as the absence of germs on direct examination and a 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. This endpoint will be measured to determine the effectiveness of the treatment in eradicating bacteria.

Secondary endpoints include the clinical cure rate, which is defined as the disappearance of clinical signs suggestive of pneumonia, resolution of biological inflammatory syndrome, and correction of haematosis disorders by D5. Additionally, the persistence rate of pneumonia will be evaluated, defined as the presence of the pathogen identified at a significant level on culture of tracheal aspirate at D5. Other secondary measures include the difference in CPIS score and ultrasound lung ventilation score between D5 and randomization, quantification and analysis of adverse events, pharmacokinetic analysis of plasma concentrations of piperacillin-tazobactam, and measurement of the ratio of penetration into alveolar fluid of piperacillin-tazobactam in patients undergoing VA-ECMO after 2 days of intravenous antibiotic therapy.