Two Randomised Controlled Trials of Inhaled Liposomal Ciprofloxacin (ARD-3150) in Patients with Non-Cystic Fibrosis Bronchiectasis and Chronic Lung Infection with Pseudomonas Aeruginosa

Abstract

Background: In patients with non-cystic fibrosis bronchiectasis (NCFB), lung infection with Pseudomonas aeruginosa is associated with severe disease, frequent pulmonary exacerbations (PEs) and hospitalisations, reduced quality of life, and higher mortality. Although inhaled antibiotics are conditionally recommended for long-term management of NCFB with frequent exacerbations, there is no approved therapy. The safety and efficacy of inhaled, liposomal ciprofloxacin (ARD-3150) was investigated in two phase III trials. Methods: ORBIT-3 (NCT01515007) and ORBIT-4 (NCT02104245) were randomised (2:1), double-blind, placebo-controlled trials in patients with NCFB and P. aeruginosa lung infection with at least two PEs requiring antibiotics in the prior year. Inhaled ARD-3150 or placebo was self-administered once daily for six cycles of 28 days on-treatment/28 days off-treatment, for 48 weeks. Findings: In ORBIT-3, 183 patients received ARD-3150 and 95 received placebo; in ORBIT-4 206 patients received ARD-3150 and 98 received placebo. Median time to first PE (primary endpoint) was significantly delayed in ORBIT-4 only (treatment effect hazard ratio [HR with 95% confidence interval (CI)] 0·72 [0·53-0·97], p=0·032; ORBIT-3 HR 0·99 [0·71-1·38], p=0·974; pooled analysis HR 0·82 [0·65-1·02], p=0·074). Frequency of PEs was not significantly reduced in ORBIT-3; however, the frequency of all severities of PEs was significantly reduced in ORBIT-4 and the pooled analysis. Sputum density of P. aeruginosa was significantly reduced with ARD-3150 at end of on-treatment periods in both trials. The safety and tolerability of ARD-3150 was similar to placebo. Interpretation: ARD-3150 may provide benefit to patients with NCFB with chronic P. aeruginosa lung infections and frequent exacerbations. Funding: Aradigm Corporation. Declaration of Interest: CSH reports personal fees from Aradigm Corporation, personal fees from Grifols, during the conduct of the study; and reports personal fees from Chiesi, personal fees from Gilead, personal fees from GlaxoSmithKline, personal fees and grants from Insmed, personal fees and grants from Teva, personal fees and grants from Vertex, personal fees from Zambon, outside of the submitted work. DB reports personal fees from Aradigm Corporation, during the conduct of the study. JDC reports personal fees with Aradigm Corporation, grants from AstraZeneca, personal fees and grants from Bayer Healthcare, personal fees and grants from BoehringerIngelheim, personal fees and grants from GlaxoSmithKline, personal fees and grants from Grifols, Ethical Approval: The trial protocols were approved at each site by an ethics committee or institutional review board. Patients provided written informed consent at enrolment.