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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

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Abstract

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.

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Notes

  1. 1 The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgments

The authors would like to thank Chiesi Farmaceutici S.p.A. (Parma, Italy) for their support in conducting this trial, and MDS Pharma Services (Paris, France) for the study implementation and periodic monitoring of the trial. The sponsor is indebted to Prof. A. Chuchalin, Scientific Research Pulmonology Institute, Russian State Medical University, Moscow, Russia and Prof. H. Mazurek, Bronchiology and Cystic Fibrosis Center, Department of National Research Institute for Tuberculosis and Lung Diseases, Rabka Hospital, Poland for their contributions to the study design as well as their review of the manuscript, and to the patients and their families for their participation in the study.

In addition to the main investigators, the following authors participated in the study: F. Gönzi (Kenézy Hospital, Debrecen, Hungary), K. Holics (Heim Pál Hospital, Budapest, Hungary), E. Sólyom (Miskolc Country Hospital, Miskolc, Hungary), G. Dobra (Petz Aladar County Hospital, Gyor, Hungary), T. Dolinay (Josa Andras Kohraz Gyermekosztaly, Nyiregyhaza, Hungary), A. Szabo (Children’s Hospital, Szeged, Hungary), J. Kus (I Klinika Chorob Pluc Instytutu Gruzlicy I Chorob Pluc, Warszawa, Poland), M. Kaczmarski (III Klinika Chorob Dzieci AM w Bialymstoku, Bialystok, Poland), J. Alkiewicz (Department of Pediatric Pneumonology and Allergic Diseases, Poznań, Poland), T. Latoś (Rehabilitation Department, Institute of Mother and Child, Karpacz, Poland), W. Mŧynarczyk (Department of Lung Diseases, Medical Academy, Poznań, Poland), I. Stelmach (Marie Skŧodowska Curie Hospital, Department of Pediatrics and Allergology, Lodz, Poland), T. Gembitskaya (Scientific Research Pulmonological Institute of St. Petersburg, State Medical University, St. Petersburg, Russia), A. Orlov (St. Olga City Pediatric Hospital, Pulmonological Department, St. Petersburg, Russia).

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Authors and Affiliations

  1. Scientific Research Pulmonology Institute, Russian State Medical University, Moscow, Russia

    Alexander Chuchalin

  2. National Institute for Pulmonology, Budapest, Hungary

    Eszter Csiszér

  3. Pulmonology Hospital, Mosdós, Hungary

    Kàlmàn Gyurkovics

  4. Cystic Fibrosis Center, Specialistic Mother and Child Care Center, Gdansk, Poland

    Maria Trawińska Bartnicka

  5. Pediatric Department, Cystic Fibrosis Center, Institute of Mother and Child, Warsaw, Poland

    Dorota Sands

  6. Scientific Clinical Department of Cystic Fibrosis, State Scientific Medical-Genetic Center RAMS, Moscow, Russia

    Nikolai Kapranov

  7. Corporate Clinical Development, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100, Parma, Italy

    Guido Varoli & Pier Alessandro Monici Preti

  8. Bronchiology and Cystic Fibrosis, Department of National Research Institute for Tuberculosis and Lung Diseases, Rabka, Poland

    Henryk Mazurek

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  1. Alexander Chuchalin
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Correspondence to Pier Alessandro Monici Preti.

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Chuchalin, A., Csiszér, E., Gyurkovics, K. et al. A Formulation of Aerosolized Tobramycin (Bramitob®) in the Treatment of Patients with Cystic Fibrosis and Pseudomonas aeruginosa Infection. Pediatr-Drugs 9 (Suppl 1), 21–31 (2007). https://doi.org/10.2165/00148581-200709001-00004

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