Original Research Article

Pediatric Drugs

, Volume 9, Issue 1, pp 21-31

A Formulation of Aerosolized Tobramycin (Bramitob®) in the Treatment of Patients with Cystic Fibrosis and Pseudomonas aeruginosa Infection

A Double-Blind, Placebo-Controlled, Multicenter Study
  • Alexander ChuchalinAffiliated withScientific Research Pulmonology Institute, Russian State Medical University
  • , Eszter CsiszérAffiliated withNational Institute for Pulmonology
  • , Kàlmàn GyurkovicsAffiliated withPulmonology Hospital
  • , Maria Trawińska BartnickaAffiliated withCystic Fibrosis Center, Specialistic Mother and Child Care Center
  • , Dorota SandsAffiliated withPediatric Department, Cystic Fibrosis Center, Institute of Mother and Child
  • , Nikolai KapranovAffiliated withScientific Clinical Department of Cystic Fibrosis, State Scientific Medical-Genetic Center RAMS
  • , Guido VaroliAffiliated withCorporate Clinical Development, Chiesi Farmaceutici S.p.A.
  • , Pier Alessandro Monici PretiAffiliated withCorporate Clinical Development, Chiesi Farmaceutici S.p.A. Email author 
  • , Henryk MazurekAffiliated withBronchiology and Cystic Fibrosis, Department of National Research Institute for Tuberculosis and Lung Diseases

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Background and aim Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) causes progressive deterioration in lung function. The purpose of this trial was to assess the efficacy and tolerability of a tobramycin highly concentrated solution for inhalation (TSI) [300mg/4mL; Bramitob®] when added to other antipseudomonal therapies in CF patients with chronic P. aeruginosa infection.

Methods In a multinational, double-blind, multicenter study, CF patients with chronic P. aeruginosa infection were randomized to receive nebulized tobramycin or placebo over a 24-week study period in which 4-week treatment periods (‘on’ cycles) were followed by 4-week periods without treatment (‘off’ cycles). Forced expiratory volume in 1 second (FEV1) percentage of predicted normal was used as the primary efficacy outcome parameter. Forced vital capacity (FVC), forced expiratory flow at 25–75% of FVC (FEF25–75%), P. aeruginosa susceptibility, minimum concentration required to inhibit 90% of strains (MIC90), rates of P. aeruginosa-negative culture, P. aeruginosa persistence and superinfection, need for hospitalization and parenteral antipseudomonal antibiotics, loss of school/working days due to the disease, and nutritional status (bodyweight and body mass index) were considered as secondary efficacy outcome parameters. Adverse events reporting, audiometry, and renal function were monitored to evaluate the tolerability and safety of TSI.

Results A total of 247 patients were randomized in the study. At endpoint time assessment (week 20), FEV1 was significantly increased in the tobramycin group and the adjusted mean difference between groups (intention-to-treat population) was statistically significant (p < 0.001). At the same time, clinically relevant improvements in FVC and FEF25–75% were detected in the TSI group (p = 0.022 and p = 0.001, respectively). The microbiologic outcomes at the end of the last ‘on’ cycle period were significantly better in the TSI group than the placebo group (p = 0.024), although there was a concomitant trend toward an increase in the MIC of isolated P. aeruginosa strains. The percentage of patients hospitalized as well as the need for parenteral antipseudomonal antibiotics was significantly lower in the TSI group (p = 0.002 and p = 0.009, respectively). Patients treated with TSI had fewer lost school/working days due to the disease (p < 0.001). A favorable effect of tobramycin in terms of an increase in bodyweight and body mass index was also noted, when compared with placebo, at all timepoints (p < 0.01 and p < 0.001, respectively). No significant changes in serum creatinine and auditory function were detected. The proportion of patients with drug-related adverse events was 15% in both treatment groups.

Conclusions Long-term, intermittent administration of this aerosolized tobramycin formulation (300mg/4mL) in CF patients with P. aeruginosa chronic infection significantly improved pulmonary function and microbiologic outcome, decreased hospitalizations, increased nutritional status, and was well tolerated.