Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection.

BACKGROUND: . In CLEAR-108-a phase 3, randomised, open-label study-once-daily amikacin liposome inhalation suspension (ALIS) was noninferior to twice-daily tobramycin inhalation solution (TIS) in improving lung function in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection after 3 treatment cycles (28 days on/28 days off). The CLEAR-110 extension study (ClinicalTrials.gov: NCT01316276; EudraCT: 2011-000443-24) assessed long-term safety, tolerability, and efficacy of ALIS in eligible patients who completed CLEAR-108. METHODS: . Patients received once-daily ALIS 590 mg for 12 treatment cycles (96 weeks). Patients were grouped by prior treatment: the "prior-ALIS" cohort received ALIS in CLEAR-108, and the "ALIS-naive" cohort received TIS in CLEAR-108. RESULTS: . Overall, 206 patients (prior-ALIS, n=92; ALIS-naive, n=114) entered CLEAR-110 and received ≥1 dose of ALIS. Most patients (88.8%) experienced ≥1 treatment-emergent adverse event (TEAE) through day 672 (end of year 2). Most TEAEs (72.3%) were mild or moderate in severity. Severe TEAEs were reported in 31 patients (15.0%). Two life-threatening TEAEs (haemoptysis; intestinal obstruction) and 1 death (cardiac failure) were reported. Twenty-one patients (10.2%) discontinued treatment due to a TEAE (mostly infective pulmonary exacerbation of CF). Mean change from baseline in forced expiratory volume in 1 second percent predicted at day 672 was -3.1% (prior-ALIS, -4.0%; ALIS-naive, -2.3%). Mean change from baseline in sputum density of P. aeruginosa at day 672 was 0.02 (prior-ALIS, -0.16; ALIS-naive, 0.19) log CFU/g. CONCLUSIONS: . Long-term treatment with ALIS was well tolerated with a favourable adverse event profile and demonstrated continued antibacterial activity in CF patients with chronic P. aeruginosa infection.

Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis.

BACKGROUND: Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. METHODS: Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). RESULTS: The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, -4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. CONCLUSIONS: Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678.

One-year safety and efficacy of tobramycin powder for inhalation in patients with cystic fibrosis.

UNLABELLED: This is an integrated analysis of data from patients with cystic fibrosis (CF) aged 6-21 years who were treated with up to seven cycles of tobramycin powder for inhalation (TIP(TM) ) over a period of at least 1 year. Safety and key efficacy endpoints were analyzed. RESULTS: The improvement in lung function and decrease in sputum P. aeruginosa (Pa) density from baseline were sustained over the 1-year treatment period. The number of adverse events (AEs) was low and did not increase with additional cycles of TIP treatment. Some increase in tobramycin minimum inhibitory concentration (MIC) was observed, but there was no significant increase in emergence of resistant strains based on the parenteral breakpoint for tobramycin. CONCLUSION: Efficacy of TIP was maintained for up to seven cycles. Long-term treatment with TIP was generally safe and well tolerated with no increase in AEs.

Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial.

BACKGROUND: Tobramycin inhalation powder (TIP) was reported to be effective in two Phase III studies in patients with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa (Pa). The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6-21 years. METHODS: CF patients with a forced expiratory volume in 1 second (FEV1) ≥25% to ≤80% predicted, positive Pa cultures and inhaled antipseudomonal therapy naïve (or at least for past 4 months) were enrolled into this double-blind, multicenter trial. Patients were randomized to receive TIP or placebo (1:1) twice daily for one treatment cycle (28.5 days on drug, 28 days off drug). The primary endpoint was relative change in FEV1 percentage predicted from baseline to day 29. A pre-specified sensitivity analysis evaluated absolute change in FEV1% predicted. Other endpoints included Pa sputum density and safety. RESULTS: A total of 62 patients out of a target of 100 (mean age 12.9 years, baseline FEV1 59.2% predicted, Pa sputum density 7.4 log10 colony forming units [CFU] per gram) were randomized. Mean treatment differences (TIP - placebo) were 5.9% (p=0.148) and 4.4% (p<0.05) for relative and absolute change in FEV1% predicted respectively. TIP significantly reduced Pa sputum density by -1.2 log10 CFU (p=0.002). Treatment with TIP was well tolerated. CONCLUSIONS: Relative change in FEV1% predicted with TIP treatment was in the expected range based on the literature, but did not reach statistical significance versus placebo. Placebo control and use of treatment naïve patients led to significant recruitment challenges and an underpowered study with consequent impact on the generated data. However, significant improvements in other outcomes including absolute change in FEV1% predicted and reduction in Pa sputum density indicate that TIP is efficacious and well tolerated in CF patients. CLINICALTRIALS.GOV IDENTIFIER: NCT00918957.