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

Abstract

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.

Keywords: ALIS; Amikacin liposome inhalation suspension; CFQ-R; Cystic fibrosis; LAI; Liposomal amikacin for inhalation; Pseudomonas aeruginosa.

Figure 1.. CLEAR-108 study design.

Patients visited the study site on days 1, 14, 28, 57, 84, 113, 140, and 168; between study visits, patients were followed by telephone contact (days 7, 21, 42, 63, 70, 77, 98, 119, 126, 133, and 154). ALIS, amikacin liposome inhalation suspension; CF, cystic fibrosis; CFU, colony-forming units; FEV₁, forced expiratory volume in 1 second; HRQoL, health-related quality of life; PFT, pulmonary function testing; PRO, patient-reported outcome; TIS, tobramycin inhalation solution.

Figure 2.. Primary endpoint of relative change from baseline to day 168 in FEV₁ (per-protocol population).

^a LS mean difference (ALIS–TIS) adjusted for treatment and randomisation strata at day 168 was −1.31% (95% CI −4.95 to 2.34; P = .48). The lower bound of the 95% CI was > −5%, indicating noninferiority of ALIS to TIS. ALIS, amikacin liposome inhalation suspension; FEV₁, forced expiratory volume in 1 second; LS, least squares; TIS, tobramycin inhalation solution.

Figure 3.. Change from baseline in sputum density of Pseudomonas aeruginosa (mITT population).

^a LS mean difference (ALIS–TIS) adjusted for treatment and randomisation strata at day 168, P=.13. ALIS, amikacin liposome inhalation suspension; CFU, colony-forming units; LS, least squares; mITT, modified intention-to-treat; TIS, tobramycin inhalation solution.