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

This study is not yet open for participant recruitment.
See Contacts and Locations
Verified August 2016 by Virginie ESCABASSE, Centre Hospitalier Intercommunal Creteil
Sponsor:
Collaborator:
Henri Mondor University Hospital
Information provided by (Responsible Party):
Virginie ESCABASSE, Centre Hospitalier Intercommunal Creteil
ClinicalTrials.gov Identifier:
NCT02888730
First received: June 22, 2016
Last updated: August 30, 2016
Last verified: August 2016
  Purpose
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

Condition Intervention Phase
Cystic Fibrosis Rhinosinusitis Lung Diseases Drug: Tobramycin nebulized nasally Drug: Physiologic serum nebulized nasally Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Virginie ESCABASSE, Centre Hospitalier Intercommunal Creteil:

Primary Outcome Measures:
  • Density of bacteria (in CFU/g log10) in sinus ostia of middle meatus samples at day 15 [ Time Frame: 15 days ]

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

Estimated Enrollment: 86
Study Start Date: September 2016
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tobramycin nebulized nasally
Nebulized Tobramycin, one bulb (tobramycin 300 mg and sodium chloride 11.25 mg) nasally twice a day for 15 days
Drug: Tobramycin nebulized nasally
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.
Other Name: Tobramycin
Placebo Comparator: Physiologic serum nebulized nasally
Nebulized sodium chloride 0.9%, one bulb twice a day nasally for 15 days
Drug: Physiologic serum nebulized nasally
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
Other Name: sodium chloride 0.9%

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

Ages Eligible for Study:   7 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02888730

Contacts
Contact: Virginie ESCABASSE, MD 1 45 17 55 97 ext 33 virginie.escabasse@chicreteil.fr
Contact: Sandrine Lacour, PhD 1 57 02 23 98 ext 33 sandrine.lacour@chicreteil.fr

Locations
France
Centre Hospitalier Universitaire de Clermont ferrand Not yet recruiting
Clermont Ferrand, France, 63003
Contact: Laurent Gilain, MD PhD       lgilain@chu-clermontferrand.fr   
Principal Investigator: Laurent Gilain, MD PhD         
Sub-Investigator: Andre Labbe, MD PhD         
Sub-Investigator: Thierry Mom, MD         
Sub-Investigator: Nicolas Saroul, MD         
Sub-Investigator: Marie Christine Heraud, MD         
Sub-Investigator: Sylvie Montcouquiol, MD         
Centre Hospitalier Intercommunal de Créteil Not yet recruiting
Creteil, France, 94000
Contact: Sandrine LACOUR, PhD    33 1 57 02 23 98    sandrine.lacour@chicreteil.fr   
Principal Investigator: Virginie Escabasse, MD PhD         
Sub-Investigator: Andre Coste, MD PhD         
Sub-Investigator: Ralph Epaud, MD         
Sub-Investigator: Bruno Housset, MD PhD         
Sub-Investigator: Laurence Bassinet, MD         
Centyre Hospitalier Universitaire de la Timone Not yet recruiting
Marseille, France, 13385
Contact: Justin Michel, MD       justin.michel@ap-hm.fr   
Principal Investigator: Justin Michel, MD         
Sub-Investigator: Jean Christophe Dubus, MD PhD         
Sub-Investigator: Richard Nicollas, MD         
Sub-Investigator: Martine Reynaud Gaubert, MD PhD         
Sub-Investigator: Patrick Dessi, MD PhD         
Sub-Investigator: Laurent Mely, MD         
Sub-Investigator: Nadine Dufeu, MD         
Centre Hospitalier Universitaire De Nantes
Nantes, France, 44093
Centre Hosiptalier de Nice Not yet recruiting
Nice, France, 06002
Contact: Sylvie Leroy, MD       leroy.s2@chu-nice.fr   
Principal Investigator: Sylvie Leroy, MD         
Sub-Investigator: Sonanda Bailleux, MD         
Sub-Investigator: Laurent Castillo, MD PhD         
Sub-Investigator: carole Bailly, MD         
Centre Hospitalier Universitaire de Toulouse Not yet recruiting
Toulouse, France, 31059
Contact: Josiane Percodani, MD       percodani.j@chu-toulouse.fr   
Principal Investigator: Josiane Percodani, MD         
Sub-Investigator: Elie Serrano, MD PhD         
Sub-Investigator: Marie Noelle Calmels, MD         
Sub-Investigator: Marlène Murris, MD         
Sub-Investigator: Laurent Tetu, MD         
Sub-Investigator: François Bremont, MD         
Sub-Investigator: Géraldine Labouret, MD         
Sub-Investigator: Marie Mittaine, MD         
Sponsors and Collaborators
Virginie ESCABASSE
Henri Mondor University Hospital
Investigators
Principal Investigator: Virginie Escabasse, MD Creteil Hospital center (CHIC)
  More Information

Publications:

Responsible Party: Virginie ESCABASSE, MD, PhD, Centre Hospitalier Intercommunal Creteil
ClinicalTrials.gov Identifier: NCT02888730     History of Changes
Other Study ID Numbers: AVASMUC
Study First Received: June 22, 2016
Last Updated: August 30, 2016
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Virginie ESCABASSE, Centre Hospitalier Intercommunal Creteil:
cystic fibrosis
chronic rhinosinusitis
Lung Diseases
tobramycin
nebulized sonic aerosol therapy

Additional relevant MeSH terms:
Fibrosis
Cystic Fibrosis
Lung Diseases
Sinusitis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Paranasal Sinus Diseases
Nose Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases
Tobramycin
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on June 23, 2017