The primary objective of the AMIVAT trial is to assess whether a 5-day course of inhaled amikacin, compared to placebo, reduces the incidence of progression to ventilator-associated pneumonia (VAP) at day 28 in intensive care unit (ICU) patients with ventilator-associated tracheobronchitis (VAT). Transition from VAT to VAP will be defined as the occurrence of a first VAP episode due to the same pathogens than those responsible for VAT.
VAT will be defined using the following criteria: (i) duration of mechanical ventilation \> 48 hours, (ii) purulent tracheobronchial secretions, (iii) no new or progressive persistent pulmonary infiltrate on chest X-ray, and (iv) bacterial growth on endotracheal aspirate (ETA) ≥10.5 colony-forming unit (CFU)/mL or on bronchoalveolar lavage ≥10.4 CFU/mL or on plugging telescopic catheter ≥10.3 CFU/mL. Inclusion and randomization will be performed after written informed consent, as soon as inclusion criteria are met, within 24 hours after VAT suspicion (ETA sampling) whenever possible. Patients in the experimental group will receive inhaled amikacin (once daily, 20 mg/kg of predicted body weight with a maximum of 2 grams) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer). Patients in the control group will receive inhaled placebo (NaCl 0.9%, once daily) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer). Nebulization will be performed according to a standardized procedure using a vibrating mesh nebulizer (Aerogen Solo, Aerogen, Galway, Ireland). A bedside checklist will be used to ensure optimal implementation practice. All staff involved in nebulization will be trained prior to their study involvement. The systemic diffusion and pharmacokinetics of inhaled amikacin will be assessed through measurement of peak and residual blood concentrations in a pre-planned subsample of patients. Study treatment will be discontinued before the 5th administration in the following cases: (i) documented acquired amikacin resistance in at least one pathogen responsible for VAT, (ii) occurrence of VAP before Day 5, (iii) occurrence of AKI stage 2 or 3 of the KDIGO classification before Day 5 (except for patients receiving renal replacement therapy), (iv) clinical indication for mandatory IV aminoglycoside therapy (amikacin, gentamicin, tobramycin) before Day 5, (v) extubation before Day 5, (vi) unexpected SAE deemed related to the IP and/or a patient's clinical condition that requires suspension of the treatment according to the local investigator. Patients will be followed-up until Day 28 for the primary study endpoint and up to Day 90 for certain secondary study endpoints (Day-90 mortality, and day-90 health-related quality of life \[HRQoL\] in survivors).
Patients in the experimental group will receive inhaled amikacin (once daily, 20 mg/kg of predicted body weight with a maximum of 2 grams) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer).
Patients in the control group will receive inhaled placebo (NaCl 0.9%, once daily) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer).
06 - ANGERS - Intensive care, University Hospital
Angers, France
04 - ARGENTEUIL - Intensive care, University Hospital
Argenteuil, France
Incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at day 28
Transition from VAT to VAP will be defined as the occurrence of a first VAP episode due to the same pathogens than those responsible for VAT
Time frame: From randomization to day 28
Incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at day 7
Transition from VAT to VAP will be defined as the occurrence of a first VAP episode due to the same pathogens than those responsible for VAT
Time frame: From randomization to day 7
Overall incidence of a first ventilator-associated pneumonia episode (all pathogens) at day 28
Time frame: From randomization to day 28
Overall incidence of a first ventilator-associated pneumonia episode due to multidrug-resistant bacteria at day 28
Time frame: From randomization to day 28
Time to resolution of clinical signs of ventilator-associated tracheobronchitis
Purulent tracheal aspirates, plus leukocytosis or leukopenia and/or fever or hypothermia if present at randomization
Time frame: From randomization to day 28
Proportion of patients with persistence of the pathogens responsible for ventilator-associated tracheobronchitis on endotracheal aspirate at day 7
Time frame: Day 7
Total duration of mechanical ventilation
Number of days with mechanical ventilation
Time frame: From randomization to day 90
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
250
11 - BLOIS, Intensive care, Hospital
Blois, France
09 - BOURG-EN-BRESSE, Intensive care, Hospital
Bourg-en-Bresse, France
10 - HENRI MONDOR, Intensive care, University Hospital
Créteil, France
07 - DIEPPE - Intensive care, University Hospital
Dieppe, France
08 - DIJON - Intensive care, University Hospital
Dijon, France
12 - DREUX, Intensive care, Hospital
Dreux, France
14 - VERSAILLES, Intensive care, Hospital
Le Chesnay, France
05 - LE MANS - Intensive care, University Hospital
Le Mans, France
...and 7 more locations
Number of ventilator-free days at day 28
Time frame: From randomization to day 28
The number of days with systemic antibiotics at Day 28
i.e., intravenous and/or enteral administration
Time frame: From randomization to day 28
Number of defined daily doses of systemic antibiotics at day 28
i.e., intravenous and/or enteral administration
Time frame: From randomization to day 28
Incidence of intensive care unit-acquired intestinal colonization with multidrug-resistant bacteria at day 28
Time frame: From randomization to day 28
Overall incidence of Intensive care unit-acquired infection due to multidrug-resistant bacteria at day 28
Time frame: From randomization to day 28
Lenght of stay in the intensive care unit
Time frame: From randomization to day 90
Lenght of hospital stay
Time frame: From randomization to day 90
All-cause mortality at day 28
Time frame: From randomization to day 28
All-cause mortality at day 90
Time frame: From randomization to day 90
Health-related quality of life at day 90
EuroQuol-5 Dimensions-5 Levels standardised questionnaire (5Q-5D-5L). Health state will be converted into a utility values using the appropriate weight in each country. Health state EQ-5D values range from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher scores indicating higher health utility.
Time frame: Day 90
Incidence of acute kidney injury at day 28
Safety analysis
Time frame: From randomization to day 28
Occurrence of respiratory adverse events related to amikacin nebulization
Safety analysis
Time frame: From randomization to day 90
Peak serum amikacin concentration 1 hour after inhaled study-drug nebulization
Pre-planned subsample. Blood samples will be collected in 50 selected patients, 25 per arm to preserve blinding For each patient included in this substudy, one sample will be collected 1 hour after the preceding nebulization to measure the peak serum amikacin concentration.
Time frame: At Day 1, Day 3 and Day 5.
Trough serum amikacin concentration 24 hours after inhaled study-drug nebulization.
Blood samples will be collected in 50 selected patients, 25 per arm to preserve blinding. For each patient included in this substudy, two samples will be collected 24 hours after the preceding nebulization to measure trough serum amikacin concentrations, for a total of 3 samples per patient.
Time frame: At Day 1, Day 3 and Day 5.