A multicentre, double-blind, randomized controlled trial of inhaled amikacin versus placebo in critically ill patients with ventilator-associated tracheobronchitis (AMIVAT)

This clinical trial evaluates the efficacy and safety of inhaled amikacin in critically ill patients with ventilator-associated tracheobronchitis (VAT). The primary objective is to determine whether a 5-day course of inhaled amikacin, compared to placebo, reduces the risk of progression to ventilator-associated pneumonia (VAP) at Day 28 in intensive care unit (ICU) patients with VAT. This objective addresses a clinically significant concern, as progression from VAT to VAP is associated with increased morbidity, prolonged mechanical ventilation, and higher healthcare resource utilization in critically ill patients.

The secondary objectives assess multiple clinical outcomes:

• Prevention of VAT progression to VAP at Day 7
• Reduction in overall incidence of first VAP episode (all pathogens) at Day 28
• Reduction in incidence of first VAP episode due to multidrug-resistant bacteria (MDRB) at Day 28
• Acceleration of resolution of clinical signs of VAT
• Clearance of VAT-causing pathogens in tracheobronchial secretions at Day 7
• Reduction in mechanical ventilation duration
• Increase in ventilator-free days at Day 28
• Reduction in exposure to systemic antibiotics (intravenous and/or enteral) at Day 28
• Reduction in incidence of ICU-acquired intestinal colonization with MDRB at Day 28
• Reduction in overall incidence of ICU-acquired infection due to MDRB at Day 28
• Reduction in ICU and hospital length of stay
• Reduction in all-cause mortality at Day 28 and Day 90
• Improvement in health-related quality of life at Day 90
• Evaluation of respiratory safety of inhaled amikacin
• Evaluation of renal safety, specifically incidence of acute kidney injury at Day 28
• Description of pharmacokinetics of inhaled amikacin in a pre-planned subsample

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of **adult patients** aged 18 years and older who were admitted to the **Intensive Care Unit (ICU)** and experienced their first episode of **ventilator-associated tracheobronchitis (VAT)** during their ICU stay. Both **male and female** subjects were eligible for participation. The trial population was selected based on specific clinical criteria, including patients requiring mechanical ventilation who developed tracheobronchitis associated with ventilator use. Women of childbearing potential were required to have a negative pregnancy test at inclusion and utilize an acceptable method of contraception throughout the study period. The trial did not involve vulnerable populations. Participants were required to be covered by the French health insurance system, and informed consent was obtained either from the patient directly or from their legally designated representative when the patient was unable to provide consent.

This clinical trial is a **multicentre**, **double-blind**, **randomized controlled trial** designed to evaluate the efficacy and safety of **inhaled amikacin** compared to **placebo** in critically ill patients with **ventilator-associated tracheobronchitis**. The study follows a **Phase III** superiority design with parallel arms. The trial aims to assess whether a 5-day course of inhaled amikacin reduces the risk of progression to **ventilator-associated pneumonia** at Day 28 in **intensive care unit** patients with ventilator-associated tracheobronchitis. The investigational medicinal product, **AMIKACINE VIATRIS 1 g**, powder for solution for injection, will be administered via **inhalation** using the **Aerogen Solo Nebulizer System**, a disposable vibrating mesh nebulizer integrated within the ventilator circuit. The maximum daily dose is 20 mg/kg with a maximum total dose of 2 g administered over a treatment period of 5 days. The placebo consists of **CHLORURE DE SODIUM 0,9 % COOPER**, solution for perfusion, administered through the same nebulization system.

The trial is planned to commence recruitment in February 2026 and is estimated to conclude in May 2029. Eligible participants include adults aged 18 years or older experiencing their first episode of ventilator-associated tracheobronchitis during their intensive care unit stay, who are covered by the French health insurance system. Women of childbearing potential must have a negative pregnancy test at inclusion and use acceptable contraception methods. Written informed consent must be obtained from the patient or, if the patient is unable to provide consent, from their legally designated representative. In urgent situations where consent cannot be obtained within the therapeutic window, the investigator may proceed with inclusion.

The **primary endpoint** is the incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at Day 28. **Secondary endpoints** include the incidence of transition to ventilator-associated pneumonia at Day 7, overall incidence of a first ventilator-associated pneumonia episode at Day 28, time to resolution of clinical signs of ventilator-associated tracheobronchitis, persistence of pathogens responsible for ventilator-associated tracheobronchitis on **endotracheal aspirate** at Day 7, total duration of **mechanical ventilation**, number of ventilator-free days at Day 28, number of defined daily doses of systemic antibiotics at Day 28, incidence of intensive care unit-acquired intestinal colonization with **multidrug-resistant bacteria** at Day 28, overall incidence of intensive care unit-acquired infection due to multidrug-resistant bacteria at Day 28, intensive care unit and hospital **length of stay**, all-cause mortality rates at Day 28 and Day 90, and **health-related quality of life** in survivors at Day 90. Safety analyses will assess the occurrence of respiratory adverse events related to amikacin nebulization and the incidence of **acute kidney injury** at Day 28. A pre-planned subsample will evaluate the pharmacokinetics of inhaled amikacin.

Participant involvement extends from the screening and inclusion visit through the treatment period of 5 days, with follow-up assessments conducted at Day 7, Day 28, and Day 90. The end-of-study visit occurs at Day 90 for surviving participants. Early termination from the study may occur under conditions such as withdrawal of consent, occurrence of serious adverse events requiring discontinuation of treatment, development of contraindications to continued participation, protocol violations, or at the discretion of the investigator if continuation is deemed not in the best interest of the participant.

The experimental medication utilized in this clinical trial is **AMIKACINE VIATRIS 1 g**, presented as a powder for solution for injection in vial. The active substance is **amikacin**, which is classified as an antibiotic. Although the product is authorized as a solution for injection, in this study amikacin intravenous formulation will be administered via **inhalation**, representing a deviation from the approved route of administration and indication specified in the marketing authorization. The pharmaceutical form of the authorized product is solution for injection. The dosage regimen consists of a maximum daily dose of **20 mg/kg**, with a maximum total dose of **2 g**. The maximum treatment period is **5 days**. The frequency and specific timing of administration are determined according to the study protocol. Amikacin will be administered through **nebulization** within the ventilator circuit using the **Aerogen Solo Nebulizer System**, a disposable vibrating mesh nebulizer. This device, manufactured by Aerogen Ltd, bears **CE marking** (CE 0050) and its use for nebulization in this study is concordant with its intended use as specified in the CE marking documentation.

The comparator treatment employed in this trial is **CHLORURE DE SODIUM 0,9 % COOPER**, a **0.9% sodium chloride solution for perfusion**, which serves as **placebo**. This product functions as the control intervention in this double-blind, randomized controlled trial design. The placebo is administered using the same nebulization method and device as the experimental medication to maintain blinding integrity throughout the study. The pharmaceutical form, dosage, and administration schedule of the placebo are designed to match those of the active treatment to ensure methodological consistency and prevent unblinding of study participants and investigators.

Efficacy will be assessed through the evaluation of the incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at Day 28, which serves as the primary endpoint. Secondary efficacy endpoints include the incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at Day 7, the overall incidence of a first ventilator-associated pneumonia episode involving all pathogens at Day 28, and the overall incidence of a first ventilator-associated pneumonia episode due to multidrug-resistant bacteria at Day 28. Additional secondary endpoints encompass the time to resolution of clinical signs of ventilator-associated tracheobronchitis, persistence of the pathogens responsible for ventilator-associated tracheobronchitis on endotracheal aspirate at Day 7, total duration of mechanical ventilation, and the number of ventilator-free days at Day 28. Further efficacy parameters include the number of defined daily doses of systemic antibiotics at Day 28, the incidence of intensive care unit-acquired intestinal colonization with multidrug-resistant bacteria at Day 28, the overall incidence of intensive care unit-acquired infection due to multidrug-resistant bacteria at Day 28, intensive care unit and hospital length of stay, all-cause mortality rates at Day 28 and Day 90, and health-related quality of life in survivors at Day 90.