Efficacy and Safety of 28 or 56 Day Treatment for Pseudomonas Aeruginosa in Children With Cystic Fibrosis

This was a multi-center, open-label, two-arm, randomized study. All patients diagnosed with CF and who fulfilled the criteria for early infection with P. aeruginosa initially received tobramycin 300 mg twice a day for 28 days. At the end of the 28-day treatment period, patients who met the inclusion criteria and none of the additional exclusion criteria were randomized in a 1:1 ratio to either receive an additional 28 days of treatment with tobramycin 300 mg twice a day (56-day group) or to stop study medication (28-day group).

All randomized patients had regular study visits until a positive P. aeruginosa sample was obtained. Once P. aeruginosa had recurred, the patient entered a follow-up phase where minimal information was collected for 27 months. During the follow-up phase, patients were treated according to their physicians' discretion.

Patients who started treatment with tobramycin but were not randomized (i.e. due to a positive antibody test) and followed up during routine clinic visits. They were allowed to continue their 28-day treatment period and afterwards be treated according to their physicians' discretion.

Inclusion criteria

• Male or female patients ≥ 6 months old
• Diagnosis of cystic fibrosis (CF) based upon the following historical criteria performed prior to study participation:

• confirmed sweat chloride > 60 mEq/L by quantitative pilocarpine iontophoresis (at least 2 tests), OR
• genotype with two identifiable mutations consistent with CF.
• First or early lower respiratory tract infection with Pseudomonas (P.) aeruginosa documented by either of the following:

• first infection defined by the first P. aeruginosa isolated from sputum or deep throat cough swab culture, OR
• P. aeruginosa from sputum or deep throat cough swab culture following at least 1 year of negative cultures (documented with at least 4 negative cultures during this year and no positive cultures) and no anti-pseudomonal treatment during this 1-year period, OR
• P. aeruginosa from sputum or deep throat cough swab culture following at least 2 years of negative cultures (documented with at least 2 negative cultures per year and no positive cultures) and no anti-pseudomonal treatment during this 2-year period.
• Written informed consent by the patient and/or parent/legal guardian according to local country regulations.

Exclusion criteria

• History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycoside.
• Signs and symptoms of acute pulmonary disease, eg, pneumonia, pneumothorax.
• Administration of any investigational drug within 30 days prior to enrollment.
• Administration of loop diuretics within 7 days prior to study drug administration.
• Personal/family history of abnormal hearing, other than typical hearing loss associated with the aging process.
• Abnormal result from an audiology testing (defined as either a unilateral pure-tone audiometry test showing a threshold elevation > 20 decibels [dB] at any frequency across the frequency range 0.25-8 kHz or the absence of emission at the evoked otoacoustic emission test).
• Positive urine pregnancy test at Day 1 (Baseline) for all female patients who have reached menarche.
• Use of macrolide antibiotics as a maintenance therapy for 12 or more days during the 28 days prior to Baseline.
• Antibody titers ≥ 1000 for any of the 3 P. aeruginosa exoenzymes: Exotoxin A, alkaline protease, or elastase (status to be determined between Baseline and Day 28).