Tobramycin Delivered by Nebulized Sonic Aerosol for Chronic Rhinosinusitis Treatment of Cystic Fibrosis Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Efficacy of Antibiotic (Tobramycin) Delivered by Nebulized Sonic Aerosol for Chronic Rhinosinusitis Treatment of Cystic Fibrosis Patients: A Multicenter Double-blind Randomized Controlled Trial

Conditions
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Cystic Fibrosis, Rhinosinusitis, Lung Diseases

Intervention / Treatment
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* Drug: Tobramycin nebulized nasally
* Drug: Physiologic serum nebulized nasally


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 7 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tobramycin nebulized nasally<br>Nebulized Tobramycin, one bulb (tobramycin 300 mg and sodium chloride 11.25 mg) nasally twice a day for 15 days | Drug: Tobramycin nebulized nasally<br>* Two sonic nebulizations per day will be realized by patients: morning and evening during 15 days. There should be a maximum of 12 hours between the 2 doses but shall not be less than 6 hours. The dosage should not be adjusted to body weight. All patients will receive one ampoule of tobramycin twice a dayAmpoules of tobramycin are filled by 5 ml containing 300 mg of tobramycin and 11.25 mg of sodium chloride. Bulb should be employed in nebulizer and administered by the inhalation route approximately 15 minutes to complete.Antibiotic retained for the study, tobramycin is manufactured by the Pharmacie à Usage Interne of the Henri Mondor Hospital. The study's product will be prepared with Base Tobramycin and excipients in accordance with TOBI's composition.<br>* Other names: Tobramycin;|
| Placebo Comparator: Physiologic serum nebulized nasally<br>Nebulized sodium chloride 0.9%, one bulb twice a day nasally for 15 days | Drug: Physiologic serum nebulized nasally<br>* Two sonic nebulizations per day will be realized by patients: morning and evening during 15 days. There should be a maximum of 12 hours between the 2 doses but shall not be less than 6 hours. The dosage should not be adjusted to body weight. All patients will receive one ampoule of placebo (Nacl 0.9%) twice a day.Ampoules of placebo are filled by 5 ml containing of sodium chloride. Bulb should be employed in nebulizer and administered by the inhalation route approximately 15 minutes to complete. Placebo for the study is manufactured by the Pharmacie à Usage Interne of the Henri Mondor Hospital. Patients in placebo arm will receive 5ml of sodium chloride with the same color (light yellow transparent) as tobramycin<br>* Other names: sodium chloride 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Density of bacteria (in CFU/g log10) in sinus ostia of middle meatus samples at day 15 |  | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| density of bacteria (in CFU/g log10) in sinus ostia of middle meatus samples at day 30 and 90 |  | day 30 and day 90 | 
| Minimum inhibitor concentration of sputum bacteria to antibiotics |  | day 15, 30 and 90 | 
| Minimum inhibitor concentration of sputum bacteria to tobramycin |  | day 90 | 
| Force Vital capacity (FCV) in both groups |  | day 0 and day 30 | 
| Forced Expiratory Volume in one second (FEV1) in both groups |  | day 0 and day 30 | 
| nasal obstruction at day 90 compared to baseline |  | day 0, 15, 30 and 90 | 
| rhinorrhea compared to baseline |  | day 0, 15, 30 and 90 | 
| mucopurulent secretions compared to baseline |  | day 0, 15, 30 and 90 | 
| facial pain compared to baseline |  | day 0, 15, 30 and 90 | 
| dysosmia compared to baseline |  | day 0, 15, 30 and 90 | 
| Nasal endoscopic scores compared to baseline in both groups |  | day 0, 15, 30 and 90 | 
| Score of the SM5 quality of life questionnaire in both groups |  | day 0, 15, 30 and 90 | 
| Score of the SNOT20 quality of life questionnaire in both groups |  | day 0, 15, 30 and 90 | 
| Hearing perception of the intensity (in db) and tone (Hz) of sound waves |  | day 0 and day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cystic fibrosis, chronic rhinosinusitis, Lung Diseases, tobramycin, nebulized sonic aerosol therapy