Two, double-blind, randomized, placebo-controlled, parallel group clinical studies (Study 1 and Study 2), which randomized and dosed 306 patients, were conducted in cystic fibrosis patients with P. aeruginosa. The osmolality of the drug formulation used in these studies differed from the to-be-marketed product. To rely upon the efficacy and safety established in the placebo-controlled studies, an additional study was conducted as a bridge to the to-be-marketed drug. The bridging study assessed the efficacy and tolerability of aerosolized Tobramycin Inhalation Solution with osmolality similar to BETHKIS over a 4-week treatment in 324 patients with cystic fibrosis. Results of this study showed that the Tobramycin Inhalation Solution in this study had similar efficacy as that seen in the placebo-controlled studies.

The compressors in the placebo-controlled studies and the bridging study differed from the PARI VIOS compressor to be used with BETHKIS. In vitro cascade impaction studies demonstrated that the various compressors used in the clinical trials delivered equivalent doses and respirable fractions of the to-be-marketed BETHKIS and TOBI with the marketed compressor (PARI VIOS) when used with the same nebulizer (PARI LC Plus Reusable nebulizer).

All subjects enrolled in both efficacy studies had baseline FEV1 % predicted ≥ 40% and ≤ 80% (mean baseline FEV1 of 60% of predicted normal) and infected with P. aeruginosa. Subjects who were less than 6 years of age, or who had a baseline creatinine of ≥ 1.5 mg/dL, or who had Burkholderia cepacia isolated from sputum were excluded. A total of 190 patients, 29 in Study 1 and 161 in Study 2, received BETHKIS therapy on an outpatient basis. Of these, 55% were males and 45% were females. Eighty-two (43.2%) patients were between 6 and 12 years of age, 54 (28.4%) patients were between 13 and 17 years of age, and the remaining 54 (28.4%) patients were greater than 17 years of age. Of the patients who received BETHKIS, only 89.7% of patients in Study 1 had at least one concomitant medication, while all patients in Study 2 also received at least one concomitant medication. These concomitant medications include mucolytics, steroidal and nonsteroidal anti-inflammatory drugs, bronchodilators, rehabilitative physiotherapies and if necessary, antibiotics for bacterial infections other than P. aeruginosa.

Study 1

Study 1 was a double-blind, single cycle study that randomized 59 patients to receive BETHKIS (n=29) or placebo (n=30) for one cycle of treatment (28 days on treatment followed by 28 days off treatment). All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. All randomized patients were included in the primary analysis except for one patient who had missing baseline information. 

BETHKIS significantly improved lung function compared with placebo as measured by the absolute change in FEV1 % predicted from baseline to the end of Cycle 1 dosing in the primary analysis population. Treatment with BETHKIS and placebo resulted in absolute increases in FEV1 % predicted of 16% and 5%, respectively (LS mean difference = 11%; 95% CI: 3, 19; p=0.003). This analysis is adjusted for the covariate of baseline FEV1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV1 % predicted over eight weeks. 

Study 2

Study 2 was a randomized, double-blind, 3-cycle, placebo-controlled trial. A total of 247 eligible patients were randomized 2:1 to receive three cycles of BETHKIS (n=161) or placebo (n=86). As in Study 1, each cycle comprised 28 days on treatment followed by 28 days off treatment. All patients were ≤46 years of age (mean age 14.8 years) and 44.9% were females. In this study, two randomized patients in the placebo group were not included in the primary efficacy analysis; one withdrew consent without taking any trial medication and the other withdrew due to an adverse drug reaction. 

BETHKIS significantly improved lung function compared with placebo as measured by the absolute change in FEV1 % predicted from baseline to the end of Cycle 3 “ON” period. Treatment with BETHKIS and placebo resulted in absolute increases in FEV1 % predicted of 7% and 1%, respectively (LS mean difference = 6%; 95% CI: 3, 10; p<0.001). This analysis is adjusted for the covariate of baseline FEV1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV1 % predicted over 24 weeks from Study 2.

Figure 1: FEV1 % of Predicted Normal – Absolute Change from Baseline (Adjusted mean) - ITT Population 

In Study 2, 9.9% of patients treated with BETHKIS and 24.7% of patients who received placebo had unplanned hospitalizations due to the disease. 

Also in Study 2, 6.2% of patients treated with BETHKIS and 16.5% of placebo patients received parenteral tobramycin.