The purpose of this study is to demonstrate that Tobrineb®/Actitob®/Bramitob® is non-inferior to TOBI® in primary efficacy variable, forced expiratory volume in one second (FEV₁) percent of predicted normal, and to compare their safety in patients with cystic fibrosis and chronic infection of the lungs with P. aeruginosa.

• Drug: tobramycin
  300mg/4ml solution, via a nebuliser, over a 4-week treatment in a twice-daily regimen
  Other Name: Tobrineb®/Actitob®/Bramitob®
• Drug: tobramycin
  300mg/5 ml solution administered via nebuliser, over a 4-week treatment in a twice-daily regimen
  Other Name: TOBI®

• 1: Active Comparator
  Tobrineb®/Actitob®/Bramitob®, tobramycin 300mg/4ml solution
  Intervention: Drug: tobramycin
• 2: Active Comparator
  TOBI® Nebuliser tobramycin 300mg/5 ml solution
  Intervention: Drug: tobramycin

• Wine JJ. Cystic fibrosis: How do CFTR mutations cause cystic fibrosis? Curr Biol. 1995 Dec 1;5(12):1357-9. Review. No abstract available.
• Dodge JA, Morison S, Lewis PA, Coles EC, Geddes D, Russell G, Littlewood JM, Scott MT. Incidence, population, and survival of cystic fibrosis in the UK, 1968-95. UK Cystic Fibrosis Survey Management Committee. Arch Dis Child. 1997 Dec;77(6):493-6.
• Lucotte G, Hazout S, De Braekeleer M. Complete map of cystic fibrosis mutation DF508 frequencies in Western Europe and correlation between mutation frequencies and incidence of disease. Hum Biol. 1995 Oct;67(5):797-803.
• Bossi A, Battistini F, Braggion C, Magno EC, Cosimi A, de Candussio G, Gagliardini R, Giglio L, Giunta A, Grzincich GL, La Rosa M, Lombardo M, Lucidi V, Manca A, Mastella G, Moretti P, Padoan R, Pardo F, Quattrucci S, Raia V, Romano L, Salvatore D, Taccetti G, Zanda M. [Italian Cystic Fibrosis Registry: 10 years of activity] Epidemiol Prev. 1999 Jan-Mar;23(1):5-16. Italian.
• Yamashiro Y, Shimizu T, Oguchi S, Shioya T, Nagata S, Ohtsuka Y. The estimated incidence of cystic fibrosis in Japan. J Pediatr Gastroenterol Nutr. 1997 May;24(5):544-7.
• Imaizumi Y. Incidence and mortality rates of cystic fibrosis in Japan, 1969-1992. Am J Med Genet. 1995 Aug 28;58(2):161-8.
• Wood RE, Boat TF, Doershuk CF. Cystic fibrosis. Am Rev Respir Dis. 1976 Jun;113(6):833-78. Review. No abstract available.
• Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059-65.
• Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066-73.
• Anderson MP, Gregory RJ, Thompson S, Souza DW, Paul S, Mulligan RC, Smith AE, Welsh MJ. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202-5.
• Trapnell BC, Chu CS, Paakko PK, Banks TC, Yoshimura K, Ferrans VJ, Chernick MS, Crystal RG. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6565-9.
• Moss RB, Babin S, Hsu YP, Blessing-Moore J, Lewiston NJ. Allergy to semisynthetic penicillins in cystic fibrosis. J Pediatr. 1984 Mar;104(3):460-6.
• Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002 Sep;20(3):658-64.
• 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.
• Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999 Jan 7;340(1):23-30.
• Gilligan PH. Microbiology of airway disease in patients with cystic fibrosis. Clin Microbiol Rev. 1991 Jan;4(1):35-51. Review.
• Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5-40. Review. No abstract available.
• Pin I, Gibson PG, Kolendowicz R, Girgis-Gabardo A, Denburg JA, Hargreave FE, Dolovich J. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax. 1992 Jan;47(1):25-9.
• Henry DA, Campbell ME, LiPuma JJ, Speert DP. Identification of Burkholderia cepacia isolates from patients with cystic fibrosis and use of a simple new selective medium. J Clin Microbiol. 1997 Mar;35(3):614-9. Erratum in: J Clin Microbiol 1999 Apr;37(4):1237.
• Bauernfeind A, Rotter K, Weisslein-Pfister C. Selective procedure to isolate haemophilus influenzae from sputa with large quantities of Pseudomonas aeruginosa. Infection. 1987 Jul-Aug;15(4):278-80.
• Johansen HK, Høiby N. Seasonal onset of initial colonisation and chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis in Denmark. Thorax. 1992 Feb;47(2):109-11.

Inclusion Criteria:

• Patients of either sex aged ≥ 6;
• Clinical diagnosis of cystic fibrosis defined as: (1)Patients preferably registered in the National Registry of CF (or other documents depending on country legislation); (2) Evidence of two or more typical pulmonary clinical features observed in CF, e.g., persistent colonization/infection with typical CF pathogens, chronic cough and sputum production, persistent chest radiography abnormalities, airway obstruction, nasal polyps and/or digital clubbing;
• Positive response in the standard sweat test (sweat chloride concentration ≥ 60 mmol/l for the standard method or ≥ 80 mmol/L for a microduct technique) documented in the clinical records and/or gene mutation documented in the clinical records;
• Chronic colonization of P. aeruginosa: presence in a sputum or throat culture of a minimum of 2 positive samples for P. aeruginosa over the previous 12 months and/or presence of more than two precipitating antibodies against P. aeruginosa;
• Sputum containing P. aeruginosa susceptible to tobramycin (defined as a zone diameter ≥ 16 mm after testing with 10 µg tobramycin disk or as a minimal inhibition concentration based on microdilution testing system) as identified by local laboratory at screening visit;
• FEV₁ ≥ 40% and ≤ 80% of the predicted normal value;
• Written informed consent obtained by parents/legal representative according to local regulations)and by the patient (when appropriate).

Exclusion Criteria:

• Administration of antipseudomonal antibiotic therapy by any route in the previous 4 weeks;
• Evidence of impaired renal function (serum creatinine level ≥ 1.5 mg/dl);
• Evidence of impaired auditory function (auditory threshold in either ear above 20 dB at frequencies between 250 and 8000Hz);
• Sputum culture containing Burkholderia cepacia;
• Patients with end-stage lung disease, candidates for heart-lung transplantation;
• History of other clinically significant cardiac, renal, neurological, gastrointestinal, hepatic or endocrine disease related to cystic fibrosis, whose sequelae and/or treatment can interfere with the results of the present study;
• Female subjects: pregnant or with active desire to be pregnant, lactating mother or lack of efficient contraception in a subject with child-bearing potential (i.e., contraceptive methods other than rod containing a hormone that prevents user from getting pregnant and that will be placed under the skin, syringes that contain a contraceptive hormone, combined birth control pill, i.e., such that contains two hormones, some IUDs and sexual abstinence). A pregnancy test in urine is to be carried out in women of a fertile age at screening and at the last clinic visit;
• Known hypersensitivity to aminoglycosides;
• Patients with evidence of alcohol or drug abuse, likely to be not compliant with the study protocol or likely to be not compliant with the study treatments;
• Participation in another clinical trial with an investigational drug in the four weeks preceding the screening visit (Visit 1).