In this study, the results were not statistically significant for the primary lung function endpoint when adjusting for the covariates of age (<13 years, ≥13 years) and FEV1 % predicted at screening (< 50%, ≥ 50%) and imputing for missing data. Improvement in lung function for TOBI Podhaler compared with placebo was eva luated using the relative change in FEV1 % predicted from baseline to the end of Cycle 1 dosing. Treatment with TOBI Podhaler (8.19%) compared to placebo (2.27%) failed to achieve statistical significance in relative change in FEV1 % predicted (LS mean difference = 5.91%; 95% CI: -2.54, 14.37; p=0.167). Analyses of absolute changes in FEV1 % predicted showed LS means of 4.86% for TOBI Podhaler and 0.48% for placebo with a difference of 4.38% (95% CI:-0.17, 8.94).

Study 1

Study 1 was a randomized, open-label, active-controlled parallel arm trial. Eligible patients were randomized 3:2 to TOBI Podhaler (4 x 28 mg capsules twice daily) or TOBI (300 mg/5 mL twice daily). Treatment was administered for 28 days, followed by 28 days off therapy (one cycle) for three cycles. The total treatment period was 24 weeks. The time to administer a dose of TOBI Podhaler (10th to 90th percentiles) ranged from 2-7 minutes at the end of the dosing period for Cycle 1, and 2-6 minutes at the end of the dosing period for Cycle 3.

A total of 517 patients were randomized in Study 1 and received TOBI Podhaler (n=308) or TOBI (n=209). Patients were predominantly 20 years of age or older (mean age 25.6 years) with no inhaled antipseudomonal antibiotic use within 28 days prior to study drug administration; 45% were female and 91% were Caucasian.

The primary purpose of Study 1 was to eva luate safety. Interpretation of efficacy results in Study 1 is limited by several factors including open-label design, testing of multiple secondary endpoints, and missing values for the outcome of FEV1 % predicted. The number (%) of patients with missing values for FEV1 % predicted at Weeks 5 and 25 in the TOBI Podhaler treated group were 40 (13.0%) and 86 (27.9%) compared to 15 (7.2%) and 40 (19.1%) in the TOBI treated group. Using imputation of the missing data, the mean differences (TOBI Podhaler minus TOBI) in the percent relative change from baseline in FEV1 % predicted at Weeks 5 and 25 were -0.87 (95% CI: -3.80, 2.07) and 1.62 (95% CI: -0.90, 4.14), respectively.

15 REFERENCES
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Ninth Edition; Approved Standard. CLSI Document M7-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.
CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02-A11. CLSI, 2012.
CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100-S22. CLSI, 2012
 

16 HOW SUPPLIED/STORAGE AND HANDLING
 

16.1 How Supplied
TOBI Podhaler contains aluminum blister-packaged 28 mg TOBI Podhaler (tobramycin inhalation powder) clear, colorless hypromellose capsules with “NVR AVCI” in blue radial imprint on one part of the capsule and the Novartis logo “” in blue radial imprint on the other part of the capsule, and Podhaler devices.

Each Podhaler device consists of the inhaler body, mouthpiece, capsule cha