Study Comparing Inhaled Amikacin Versus Placebo to Prevent Ventilator Associated Pneumonia

Study Overview
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Brief Summary
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The objective of the study is to prove that after the third day of invasive mechanical ventilation a three-day course of inhaled amikacin reduces the incidence of subsequent VAP. Parallel two group double blind randomized controlled clinical trial. Individual randomization, performed on day 4 of invasive mechanical ventilation, will be stratified on centre in order to account for variations in VAP prevention bundle implementation and use of systemic antibiotics the day of randomization. Patients will be treated three consecutive days with inhaled amikacin or placebo. Patients will be followed up daily in the intensive care unit for the occurrence of VAP according to international guidelines until day 28.

Official Title
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Double-blinded Multicenter Randomized Controlled Trial Comparing Inhaled Amikacin Versus Placebo to Prevent Ventilator Associated Pneumonia

Conditions
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Pneumonia, Ventilator-Associated

Intervention / Treatment
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* Drug: Inhaled amikacin
* Drug: Inhaled placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years the day of inclusion Mechanical ventilation through an endotracheal tube for more than three consecutive days (72h) Written informed consent of the patient or a proxy Patients covered by or having the rights to French social security Negative pregnancy test, at the time of inclusion, in women of childbearing potential Exclusion Criteria: Suspicion or confirmed VAP the day of inclusion Clinical indication for systemic aminoglycoside therapy the day of inclusion : as deemed necessary by the clinician in charge Stage 2 or 3 KDIGO* classification acute kidney injury the day of inclusion excepted in patients undergoing renal replacement therapy Chronic kidney failure : baseline glomerular filtration lower than 30 mL/min Patient scheduled for extubation within the next 24h Patient ventilated through an endotracheal tube for more than four consecutive days before inclusion (96h) Patient ventilated through a tracheostomy Patients allergic to aminoglycosides Myasthenia gravis Known pregnant women at the time of inclusion and lactating patients Known guardianship or trusteeship at the time of inclusion Patients previously included in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled amikacin<br>Inhaled amikacin at day 4, day 5 and day 6 of invasive mechanical ventilation: 20 mg/kg of ideal body weight, maximum 2 g per day. | Drug: Inhaled amikacin<br>* Once a day, inhaled amikacin at day 4, day 5 and day 6 of invasive mechanical ventilation: 20 mg/kg of ideal body weight, maximum 2 g per day.<br>|
| Placebo Comparator: Placebo<br>Once a day, inhaled placebo at day 4, day 5 and day 6 of invasive mechanical ventilation. | Drug: Inhaled placebo<br>* Once a day, inhaled placebo at day 4, day 5 and day 6 of invasive mechanical ventilation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of a first VAP episode from randomization to day 28 |  | Patients will be followed from randomization to day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of a first VAP episode in the subgroups of patients with tracheobronchial colonization or tracheobronchitis |  | At randomization | 
| Incidence of VAP due to Gram negative amikacin sensitive bacteria |  | Patients will be followed from randomization to day 28 | 
| Clinical pulmonary infection score evolution |  | Patients will be followed from randomization to day 28 | 
| Ventilator associated events incidence |  | Patients will be followed from randomization to day 28 | 
| Number of systemic antibiotics administered per day |  | Patients will be followed from randomization to day 28 | 
| Number of days with at least one administration of a systemic antibiotic |  | Patients will be followed from randomization to day 28 | 
| Incidence of antibiotic resistant bacteria isolated on clinical and hygiene samples |  | Patients will be followed from randomization to day 28 | 
| Incidence of acute kidney injury |  | Patients will be followed from randomization to day 28 | 
| Days spent on mechanical ventilation from randomization to day 90 |  | Patients will be followed from randomization to day 90 | 
| Days from randomization to the first successful spontaneous breathing trial |  | Days from randomization to day 90 max | 
| Days spent in the intensive care unit and in the hospital |  | Patients will be followed from randomization to discharge (day 90 max) | 
| Day 90 mortality |  | Day 90 | 
| Incidence of bacteria producing extended spectrum beta-lactamase or high level derepressed celphalosporinase, of vancomycin resistant Enterococcus Sp. on rectal samples |  | Day 28 | 
| Relative bacterial species composition of respiratory and digestive microbiota |  | Patients will be followed from randomization to day 28 | 
| Maximum serum Concentration |  | Between Hour 0-Hour 8, between Hour 8-Hour 16 and between Hour 16-Hour 24 | 
| Maximum sputum Concentration |  | Between Hour 0-Hour 8, between Hour 8-Hour 16 and between Hour 16-Hour 24 | 
| Area Under the Curve |  | Between Hour 0-Hour 8, between Hour 8-Hour 16 and between Hour 16-Hour 24 | 
| To evaluate the effects on respiratory mechanics of nebulization of amikacin by evaluating the benefit balance / risk | benefit : Improvement of respiratory mechanics by pharmacological effect risk : Degradation of respiratory mechanics by bronchospastic secondary effect, drug deposition in the intubation probe | Measurements at 8 hours, 12 hours and 24 hours after the end of nebulization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention, inhaled amikacin, placebo