er arm (65% TOBI Podhaler vs 55% TOBI). This included oral antibiotics in 55% of TOBI Podhaler patients and 40% of TOBI patients and intravenous antibiotics in 35% of TOBI Podhaler patients and 33% of TOBI patients. Median time to first antipseudomonal usage was 89 days in the TOBI Podhaler arm and 112 days in the TOBI arm.
The supportive safety population reflects patients from two studies: Study 2, a double-blind, placebo-controlled design for the first treatment cycle, followed by all patients receiving TOBI Podhaler (replaced placebo) for two additional cycles, and Study 3, a double-blind, placebo-controlled trial for one treatment cycle only. Placebo in these studies was inhaled powder without the active ingredient, tobramycin. The patient population for these studies was much younger than in Study 1 (mean age 13 years old).
Adverse drug reactions reported more frequently by TOBI Podhaler patients in the placebo-controlled cycle (Cycle 1) of Study 2, which included 46 TOBI Podhaler and 49 placebo patients, were:
Respiratory, thoracic, and mediastinal disorders
Pharyngolaryngeal pain (TOBI Podhaler 10.9%, placebo 0%); dysphonia (TOBI Podhaler 4.3%, placebo 0%)
Gastrointestinal disorders
Dysgeusia (TOBI Podhaler 6.5%, placebo 2.0%)
Adverse drug reactions reported more frequently by TOBI Podhaler patients in Study 3, which included 30 TOBI Podhaler and 32 placebo patients, were:
Respiratory, thoracic, and mediastinal disorders
Cough (TOBI Podhaler 10%, placebo 0%)
Ear and labyrinth disorders
Hypoacusis (TOBI Podhaler 10%, placebo 6.3%)
Audiometric assessment
In Study 1, audiology testing was performed in a subset of approximately 25% of TOBI Podhaler (n=78) and TOBI (n=45) patients. Using the criteria for either ear of ≥ 10 dB loss at two consecutive frequencies, ≥ 20 dB loss at any frequency, or loss of response at three consecutive frequencies where responses were previously obtained, five TOBI Podhaler patients and three TOBI patients were judged to have ototoxicity, a ratio similar to the planned 3:2 randomization for this study.
Audiology testing was also performed in a subset of patients in both Study 2 (n=13 from the TOBI Podhaler group and n=9 from the placebo group) and Study 3 (n=14 from the TOBI Podhaler group and n=11 from the placebo group). In Study 2, no patients reported hearing complaints but two TOBI Podhaler patients met the criteria for ototoxicity. In Study 3, three TOBI Podhaler and two placebo patients had reports of ‘hypoacusis’. One TOBI Podhaler and two placebo patients met the criteria for ototoxicity. In some patients, ototoxicity was transient or may have been related to a conductive defect.
Cough
Cough is a common symptom in cystic fibrosis, reported in 42% of the patients in Study 1 at baseline. Cough was the most frequently reported adverse event in Study 1 and was more common in the TOBI Podhaler arm (48% TOBI Podhaler vs 31 % TOBI). There was a higher rate of cough adverse event reporting during the first week of active treatment with TOBI Podhaler (i.e., the first week of Cycle 1). The time to first cough event in the TOBI Podhaler and TOBI groups were similar thereafter. In some patients, cough resulted in discontinuation of TOBI Podhaler treatment. Sixteen patients (5%) receiving treatment with TOBI Podhaler discontinued study treatment due to cough events compared with 2 (1%) in the TOBI treatment group. Children and adolescents coughed more than adults when treated with TOBI Podha |
