Study Comparing Inhaled Amikacin Versus Placebo to Prevent Ventilator Associated Pneumonia (AMIKINHAL)

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

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.

Study Overview

• Status: Completed
• Conditions: Pneumonia, Ventilator-Associated
• Intervention / Treatment: Drug: Inhaled amikacin; Drug: Inhaled placebo

• Study Type: Interventional
• Enrollment (Actual): 850
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
    • Service de Réanimation Chirurgicale
  • Angoulême, France, 16959
    • Service de Réanimation Médicale - CH d'Angoulême
  • Argenteuil, France
    • Service de réanimation Polyvalente
  • Colombes, France, 92700
    • Service de Réanimation Médicale - Hôpital Louis Mourier
  • Dijon, France, 21079
    • Service de réanimation
  • La Roche-sur-Yon, France, 85025
    • Service de Réanimation Médicale - CHD Les Oudairies
  • Le Mans, France, 72037
    • Service de réanimation
  • Lyon, France, 69317
    • Service de Réanimation Médicale - Hôpital La Croix-Rousse
  • Orléans, France, 45100
    • Service de réanimation médicale
  • Paris, France, 75013
    • Service de Réanimation Médicale - Hôpital Pitié Salpêtrière
  • Poitiers, France, 86021
    • Service de Réanimation Médicale - CHU La Milétrie
  • Poitiers, France, 86021
    • Service de réanimation médicale
  • Rennes, France, 35033
    • Service de Réanimation Médicale - CHU Pontchaillou
  • Rouen, France, 76031
    • Service de Réanimation Médicale - CHU Rouen
  • Rouen, France, 76031
    • Service de Réanimation Médicale - Hôpital Charles Nicolle
  • Strasbourg, France, 67091
    • Service de Réanimation - NHC
  • Strasbourg, France, 67098
    • Service de Réanimation Médicale - Hôpital de Hautepierre
  • Tours, France, 37044
    • Service de Réanimation médicale, Hôpital Trousseau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Inhaled amikacin; 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; 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.
PLACEBO_COMPARATOR: Placebo; Once a day, inhaled placebo at day 4, day 5 and day 6 of invasive mechanical ventilation.	Drug: Inhaled placebo; Once a day, inhaled placebo at day 4, day 5 and day 6 of invasive mechanical ventilation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
Day 90 mortality		Day 90
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)
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

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Principal Investigator: Stephan EHRMANN, MD-PhD, University Hospital, Tours

Publications and helpful links

General Publications

• Tavernier E, Barbier F, Meziani F, Quenot JP, Herbrecht JE, Landais M, Roux D, Seguin P, Schnell D, Veinstein A, Veber B, Lasocki S, Lu Q, Beduneau G, Ferrandiere M, Dahyot-Fizelier C, Plantefeve G, Nay MA, Merdji H, Andreu P, Vecellio L, Muller G, Cabrera M, Le Pennec D, Respaud R, Lanotte P, Gregoire N, Leclerc M, Helms J, Boulain T, Lacherade JC, Ehrmann S; REVA network and the CRICS-TRIGGESEP F-CRIN network. Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol. BMJ Open. 2021 Sep 14;11(9):e048591. doi: 10.1136/bmjopen-2020-048591.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 19, 2017
• Primary Completion (ACTUAL): March 9, 2021
• Study Completion (ACTUAL): June 17, 2021

Study Registration Dates

• First Submitted: May 2, 2017
• First Submitted That Met QC Criteria: May 9, 2017
• First Posted (ACTUAL): May 11, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: placebo; Prevention; inhaled amikacin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Infective Agents; Anti-Bacterial Agents; Amikacin
• Other Study ID Numbers: PHRN15-SE / AMIKINHAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No