Patrick A Flume1, Donald R VanDevanter2, Elizabeth E Morgan3, Michael N Dudley3, Jeffery S Loutit3, Scott C Bell4, Eitan Kerem5, Rainald Fischer6, Alan R Smyth7, Shawn D Aaron8, Douglas Conrad9, David E Geller10, J Stuart Elborn11. 1. Departments of Medicine and Pediatrics, Medical University of South Carolina, Charleston, SC, USA. Electronic address: flumepa@musc.edu. 2. Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 3. The Medicines Company, San Diego, CA, USA. 4. The Prince Charles Hospital and QIMR Berghofer Medical Research Institute, Queensland, Brisbane, Australia. 5. Department of Pediatrics, Hadassah Medical Center, Jerusalem, Israel. 6. Pneumologische Praxis München-Pasing, Munich, Germany. 7. Division of Child Health, Obstetrics & Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK. 8. The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. 9. Department of Medicine, University of California, San Diego, CA, USA. 10. Florida State University College of Medicine, Orlando, FL, USA. 11. Centre for Infection and Immunity, Queens University Belfast, Belfast BT9 7AE, UK.
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 240mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection. METHODS: A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CF patients ≥12years 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 28days 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.
RCT Entities:
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 240mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection. METHODS: A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CFpatients ≥12years 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 28days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CFpatients with chronic P. aeruginosa.