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

NCT02888730 | Terminated Phase 3 DMC

• 1 other identifier: AVASMUC
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 6

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

Conditions

Cystic Fibrosis; Rhinosinusitis; Lung Diseases

Keywords

cystic fibrosis; chronic rhinosinusitis; Lung Diseases; tobramycin; nebulized sonic aerosol therapy

Outcome Measures

Primary Outcomes (1)

• Density of bacteria (in CFU/g log10) in sinus ostia of middle meatus samples at day 15

  15 days

Secondary Outcomes (14)

• 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

Study Arms (2)

Tobramycin nebulized nasally

EXPERIMENTAL

Nebulized Tobramycin, one bulb (tobramycin 300 mg and sodium chloride 11.25 mg) nasally twice a day for 15 days

Drug: Tobramycin nebulized nasally

Physiologic serum nebulized nasally

PLACEBO COMPARATOR

Nebulized sodium chloride 0.9%, one bulb twice a day nasally for 15 days

Drug: Physiologic serum nebulized nasally

Interventions

Tobramycin nebulized nasally DRUG

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.

Also known as: Tobramycin

Tobramycin nebulized nasally

Physiologic serum nebulized nasally DRUG

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

Also known as: sodium chloride 0.9%

Physiologic serum nebulized nasally

Eligibility Criteria

• Age: 7 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• \- 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)

Sponsors & Collaborators

• Virginie ESCABASSE: lead
• Henri Mondor University Hospital: collaborator

Study Sites (6)

Centre Hospitalier Universitaire de Clermont ferrand

Clermont-Ferrand, 63003, France

Location

Centre Hospitalier Intercommunal de Créteil

Créteil, 94000, France

Location

Centre Hospitalier Universitaire de la Timone

Marseille, 13385, France

Location

Centre Hospitalier Universitaire De Nantes

Nantes, 44093, France

Location

Centre Hosiptalier de Nice

Nice, 06002, France

Location

Centre Hospitalier Universitaire de Toulouse

Toulouse, 31059, France

Location

Related Publications (20)

• Aanaes K, von Buchwald C, Hjuler T, Skov M, Alanin M, Johansen HK. The effect of sinus surgery with intensive follow-up on pathogenic sinus bacteria in patients with cystic fibrosis. Am J Rhinol Allergy. 2013 Jan;27(1):e1-4. doi: 10.2500/ajra.2013.27.3829.

  PMID: 23406585 BACKGROUND

• Berkhout MC, Rijntjes E, El Bouazzaoui LH, Fokkens WJ, Brimicombe RW, Heijerman HG. Importance of bacteriology in upper airways of patients with Cystic Fibrosis. J Cyst Fibros. 2013 Sep;12(5):525-9. doi: 10.1016/j.jcf.2013.01.002. Epub 2013 Jan 26.

  PMID: 23357546 BACKGROUND

• Boucher RC. Human airway ion transport. Part one. Am J Respir Crit Care Med. 1994 Jul;150(1):271-81. doi: 10.1164/ajrccm.150.1.8025763. No abstract available.

  PMID: 8025763 BACKGROUND

• Boucher RC. Human airway ion transport. Part two. Am J Respir Crit Care Med. 1994 Aug;150(2):581-93. doi: 10.1164/ajrccm.150.2.8049852. No abstract available.

  PMID: 8049852 BACKGROUND

• Coste A, Gilain L, Roger G, Sebbagh G, Lenoir G, Manach Y, Peynegre R. Endoscopic and CT-scan evaluation of rhinosinusitis in cystic fibrosis. Rhinology. 1995 Sep;33(3):152-6.

  PMID: 8560168 BACKGROUND

• Digoy GP, Dunn JD, Stoner JA, Christie A, Jones DT. Bacteriology of the paranasal sinuses in pediatric cystic fibrosis patients. Int J Pediatr Otorhinolaryngol. 2012 Jul;76(7):934-8. doi: 10.1016/j.ijporl.2012.02.043. Epub 2012 Apr 17.

  PMID: 22513080 BACKGROUND

• Durand M, Pourchez J, Aubert G, Le Guellec S, Navarro L, Forest V, Rusch P, Cottier M. Impact of acoustic airflow nebulization on intrasinus drug deposition of a human plastinated nasal cast: new insights into the mechanisms involved. Int J Pharm. 2011 Dec 12;421(1):63-71. doi: 10.1016/j.ijpharm.2011.09.023. Epub 2011 Sep 21.

  PMID: 21963472 BACKGROUND

• Durand M, Le Guellec S, Pourchez J, Dubois F, Aubert G, Chantrel G, Vecellio L, Hupin C, De Gersem R, Reychler G, Pitance L, Diot P, Jamar F. Sonic aerosol therapy to target maxillary sinuses. Eur Ann Otorhinolaryngol Head Neck Dis. 2012 Oct;129(5):244-50. doi: 10.1016/j.anorl.2011.09.002. Epub 2012 Aug 24.

  PMID: 22921302 BACKGROUND

• Gysin C, Alothman GA, Papsin BC. Sinonasal disease in cystic fibrosis: clinical characteristics, diagnosis, and management. Pediatr Pulmonol. 2000 Dec;30(6):481-9. doi: 10.1002/1099-0496(200012)30:63.0.co;2-n.

  PMID: 11109061 BACKGROUND

• Hansen SK, Rau MH, Johansen HK, Ciofu O, Jelsbak L, Yang L, Folkesson A, Jarmer HO, Aanaes K, von Buchwald C, Hoiby N, Molin S. Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection. ISME J. 2012 Jan;6(1):31-45. doi: 10.1038/ismej.2011.83. Epub 2011 Jun 30.

  PMID: 21716309 BACKGROUND

• Kahl BC, Duebbers A, Lubritz G, Haeberle J, Koch HG, Ritzerfeld B, Reilly M, Harms E, Proctor RA, Herrmann M, Peters G. Population dynamics of persistent Staphylococcus aureus isolated from the airways of cystic fibrosis patients during a 6-year prospective study. J Clin Microbiol. 2003 Sep;41(9):4424-7. doi: 10.1128/JCM.41.9.4424-4427.2003.

  PMID: 12958283 BACKGROUND

• Knowles MR, Robinson JM, Wood RE, Pue CA, Mentz WM, Wager GC, Gatzy JT, Boucher RC. Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. J Clin Invest. 1997 Nov 15;100(10):2588-95. doi: 10.1172/JCI119802.

  PMID: 9366574 BACKGROUND

• Konstan MW, Morgan WJ, Butler SM, Pasta DJ, Craib ML, Silva SJ, Stokes DC, Wohl ME, Wagener JS, Regelmann WE, Johnson CA; Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr. 2007 Aug;151(2):134-9, 139.e1. doi: 10.1016/j.jpeds.2007.03.006. Epub 2007 Jun 22.

  PMID: 17643762 BACKGROUND

• Mainz JG, Naehrlich L, Schien M, Kading M, Schiller I, Mayr S, Schneider G, Wiedemann B, Wiehlmann L, Cramer N, Pfister W, Kahl BC, Beck JF, Tummler B. Concordant genotype of upper and lower airways P aeruginosa and S aureus isolates in cystic fibrosis. Thorax. 2009 Jun;64(6):535-40. doi: 10.1136/thx.2008.104711. Epub 2009 Mar 11.

  PMID: 19282318 BACKGROUND

• Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, Schidlow DV, Wilmott RW, Astley SJ, McBurnie MA, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993 Jun 17;328(24):1740-6. doi: 10.1056/NEJM199306173282403.

  PMID: 8497284 BACKGROUND

• Regnis JA, Robinson M, Bailey DL, Cook P, Hooper P, Chan HK, Gonda I, Bautovich G, Bye PT. Mucociliary clearance in patients with cystic fibrosis and in normal subjects. Am J Respir Crit Care Med. 1994 Jul;150(1):66-71. doi: 10.1164/ajrccm.150.1.8025774.

  PMID: 8025774 BACKGROUND

• Robertson JM, Friedman EM, Rubin BK. Nasal and sinus disease in cystic fibrosis. Paediatr Respir Rev. 2008 Sep;9(3):213-9. doi: 10.1016/j.prrv.2008.04.003. Epub 2008 Jul 31.

  PMID: 18694713 BACKGROUND

• Vaughan WC, Carvalho G. Use of nebulized antibiotics for acute infections in chronic sinusitis. Otolaryngol Head Neck Surg. 2002 Dec;127(6):558-68. doi: 10.1067/mhn.2002.129738.

  PMID: 12501108 BACKGROUND

• Walter S, Gudowius P, Bosshammer J, Romling U, Weissbrodt H, Schurmann W, von der Hardt H, Tummler B. Epidemiology of chronic Pseudomonas aeruginosa infections in the airways of lung transplant recipients with cystic fibrosis. Thorax. 1997 Apr;52(4):318-21. doi: 10.1136/thx.52.4.318.

  PMID: 9196512 BACKGROUND

• Karanth TK, Karanth VKLK, Ward BK, Woodworth BA, Karanth L. Medical interventions for chronic rhinosinusitis in cystic fibrosis. Cochrane Database Syst Rev. 2022 Apr 7;4(4):CD012979. doi: 10.1002/14651858.CD012979.pub3.

  PMID: 35390177 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis; Rhinosinusitis; Lung Diseases

Interventions

Tobramycin; Sodium Chloride

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Rhinitis; Respiratory Tract Infections; Infections; Sinusitis; Paranasal Sinus Diseases; Nose Diseases; Otorhinolaryngologic Diseases

Intervention Hierarchy (Ancestors)

Nebramycin; Kanamycin; Aminoglycosides; Glycosides; Carbohydrates; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Virginie Escabasse, MD

  Creteil Hospital center (CHIC)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: June 22, 2016
• First Posted: September 5, 2016
• Study Start: February 16, 2017
• Primary Completion: May 16, 2017
• Study Completion: July 8, 2019
• Last Updated: February 15, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (6)