A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

Flume, Patrick; VanDevanter, Donald R.; Morgan, E.E.; Dudley, Michael N.; Loutit, Jeffery S.; Bell, Scott C.; Kerem, Eitan; Fischer, R.; Smyth, Alan R.; Aaron, Shawn D.; Conrad, Douglas; Geller, David E.; Elborn, J. Stuart

Abstract

Rationale

For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF.
Objectives

To compare the safety and efficacy of a 28-day course of treatment with LIS 240 mg or placebo BID in persons ≥ 12 years old with CF and chronic P. aeruginosa infection.
Methods

A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28 days in CF patients ≥ 12 years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints.
Main results

Baseline demographics for 330 subjects (LIS = 220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p = 0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event.
Conclusions

LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28 days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.

Citation

Flume, P., VanDevanter, D. R., Morgan, E., Dudley, M. N., Loutit, J. S., Bell, S. C., …Elborn, J. S. (2016). A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. Journal of Cystic Fibrosis, 15, https://doi.org/10.1016/j.jcf.2015.12.004

• Journal Article Type: Article
• Acceptance Date: Dec 2, 2015
• Online Publication Date: Feb 4, 2016
• Publication Date: Jul 1, 2016
• Deposit Date: Oct 19, 2016
• Publicly Available Date: Oct 19, 2016
• Journal: Journal of Cystic Fibrosis
• Print ISSN: 1569-1993
• Electronic ISSN: 1873-5010
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 15
• DOI: https://doi.org/10.1016/j.jcf.2015.12.004
• Keywords: Cystic fibrosis; Antibiotics; Pseudomonas; Aerosol; Fluoroquinolone
• Public URL: https://nottingham-repository.worktribe.com/output/975866
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S1569199315002763?np=y