Clinical trial NCT02888730: Tobramycin Delivered by Nebulized Sonic Aerosol for Chronic Rhinosinusitis Treatment of Cystic Fibrosis Patients
Official title: Efficacy of Antibiotic (Tobramycin) Delivered by Nebulized Sonic Aerosol for Chronic Rhinosinusitis Treatment of Cystic Fibrosis Patients: A Multicenter Double-blind Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cystic Fibrosis
Rhinosinusitis
Lung Diseases
Keywords: cystic fibrosis
chronic rhinosinusitis
Lung Diseases
tobramycin
nebulized sonic aerosol therapy
Lead sponsor: Centre Hospitalier Intercommunal Creteil
Sponsor class: OTHER
Collaborators: name: Henri Mondor University Hospital
First posted: 2016-09-05
Enrollment: 86
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with cystic fibrosis frequently develop chronic rhinosinusitis. Bacterial colonization is facilitated by a reduced mucociliary function and some previous studies suggest that the microbiology of the upper airways might influence the microbiology of the lower airway. The aim of this randomized control study is to demonstrate efficacy of antibiotic delivered by nebulized sonic aerosol therapy to decrease the bacterial load in sinuses and medium ostia and to improve the sino-nasal symptoms and endoscopic scores, quality of life and lung function

Detailed description: Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in the Caucasian population affecting \~1:3000 children, with a carrier frequency of 1:25. It is a multisystem disorder where pulmonary and sinonasal involvements occur in 90-100% of patients, and up to 86% of children have nasal polyps . Patients with CF develop chronic rhinosinusitis (CRS) due to the defect in the cystic fibrosis Transmembrane Regulator (CFTR) protein. The membrane lining the paranasal sinuses and the nose is identical to the membrane lining the lungs. As in lower airways (LAW) the defect CFTR protein result in viscous mucus . Consequently mucociliary function is reduced, which facilitates bacterial colonization and eventually infection leading to rhinosinusitis . In the past decades infection of the lower airways was the most prominent focus in treatment protocols for CF. Over the years infection of the upper airways (UAW) gradually gained more attention in CF.

Previous research in the microbiology of the upper airways (UAW) in CF displayed that Haemophilus influenzae, Pseudomonas aeruginosa and Staphylococcus aureus were most frequently cultures from the UAW . Since several studies showed concordance between organisms in the UAW and the LAW in CF, the hypothesis evolved that the UAW might influence the patient pulmonary status . Moreover, comparison of UAW and and LAW cultures in CF adult patients showed that Pseudomonas aeruginosa can be cultured from the UAW after eradication therapy which may suggest persistence of Pseudomonas aeruginosa in the UAW . This problem is highlighted in double lung transplant where UAW also appears as a protective niche of adapted clones of bacteria, which can intermittently spread this pathogen to the lung.

CRS treatment in CF patients is based on daily nasal lavages but above all on local or systemic antibiotic treatments to eradicate bacteria in sinuses . Local therapy is favoured in CRS treatment of CF patients to avoid antibiotic side effects, changing organisms or resistance patterns. Sonic aerosol therapy with antibiotics for 15 days is commonly used for CRS in non CF patients to improve sinonasal symptoms and reduce purulent secretions as sound addition in pneumatic aerosol in head corpse's models creates an acoustic pressure at the ostia to improve the aerosol penetration in maxillary sinuses . However its efficacy on bacterial carrying in sinuses is not proved . At the opposite, efficacy of aerosol of tobramycin to LAW was proved in CF patients with a decrease of the density of Pseudomonas aeruginosa, an improvement of FEV, and fewer pulmonary exacerbations .

At the present time, efficacy of antibiotic (tobramycin) delivered by nebulized sonic aerosol for CRS treatment of CF patients is unknown particularly on bacterial carrying.

The aim of this study is to demonstrate that nebulized sonic aerosol therapy with tobramycin in Cystic Fibrosis patients decreases significantly bacterial carrying in sinuses, sinus ostia of middle meatus and sputum compared to nebulized sonic aerosol therapy with placebo and that nebulized sonic aerosol therapy improves sino-nasal symptoms and endoscopic scores, quality of life and lung function.

Eligibility criteria: Inclusion Criteria:

* Patients older than 7 years followed in the 6 CRCM centers (Créteil, Marseille, Nantes, Toulouse, Clermont-Ferrand and Nice). We choose to enroll children aged 7 years or more because as they have a better adherence to nebulization treatment than younger children.
* Diagnosis of cystic fibrosis confirmed by sweat test (\>60mmol/L) and/or the identification of two CF-causing mutations
* Confirmed chronic rhinosinusitis by Ear Nose and Throat doctor by endoscopic examination: bilateral mucopurulent secretions at middle meatus present longer than 12 weeks with or without nasal polyps
* Positive bacteria susceptibility to tobramycin in samples from middle meatus
* Susceptibility of bacteria to tobramycin confirmed
* Pulmonary examination before enrollment
* Written informed consent obtained at enrollment for all patients (consent of minor's parent for children)
* Social security affiliation

Exclusion Criteria:

* - Oral antibiotic therapy one month before enrollment
* enrollment in another protocol with antibiotic
* Ongoing aerosolized tobramycin for endobronchial infection to avoid an overlap between treatment for lung and treatment for sinusitis
* Abnormal auditory acuity (decrease of 20dB in auditory acuity)
* Hypersensibility or allergenecity of aminoglycosides
* FEV \< 25% or FVC of 40% or more of the value predicted for height
* Transplant patient or patient on transplant list
* Patient under nasal oxygen or under noninvasive ventilation
* Pregnant woman
* Breast-feeding
* No Social security affiliation
* Informed consent non obtained at enrollment for all patients (consent of minor's parent for children)

Primary outcomes:
measure: Density of bacteria (in CFU/g log10) in sinus ostia of middle meatus samples at day 15
timeFrame: 15 days
Secondary outcomes:
measure: density of bacteria (in CFU/g log10) in sinus ostia of middle meatus samples at day 30 and 90
timeFrame: day 30 and day 90
measure: Minimum inhibitor concentration of sputum bacteria to antibiotics
timeFrame: day 15, 30 and 90
measure: Minimum inhibitor concentration of sputum bacteria to tobramycin
timeFrame: day 90
measure: Force Vital capacity (FCV) in both groups
timeFrame: day 0 and day 30
measure: Forced Expiratory Volume in one second (FEV1) in both groups
timeFrame: day 0 and day 30
measure: nasal obstruction at day 90 compared to baseline
timeFrame: day 0, 15, 30 and 90
measure: rhinorrhea compared to baseline
timeFrame: day 0, 15, 30 and 90
measure: mucopurulent secretions compared to baseline
timeFrame: day 0, 15, 30 and 90
measure: facial pain compared to baseline
timeFrame: day 0, 15, 30 and 90
measure: dysosmia compared to baseline
timeFrame: day 0, 15, 30 and 90
measure: Nasal endoscopic scores compared to baseline in both groups
timeFrame: day 0, 15, 30 and 90
measure: Score of the SM5 quality of life questionnaire in both groups
timeFrame: day 0, 15, 30 and 90
measure: Score of the SNOT20 quality of life questionnaire in both groups
timeFrame: day 0, 15, 30 and 90
measure: Hearing perception of the intensity (in db) and tone (Hz) of sound waves
timeFrame: day 0 and day 30
Other outcomes:
Locations:
city: Clermont Ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont ferrand
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Marseille
country: France
facility: Centre Hospitalier Universitaire de la Timone
city: Nantes
country: France
facility: Centre Hospitalier Universitaire De Nantes
city: Nice
country: France
facility: Centre Hosiptalier de Nice
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
Study officials:
affiliation: Creteil Hospital center (CHIC)
name: Virginie Escabasse, MD
role: PRINCIPAL_INVESTIGATOR
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