Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis Respiratory Infections Pulmonary Cystic Fibrosis CFTR
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 49
Healthy volunteers: no

Brief summary:
A major factor in the respiratory health of cystic fibrosis (CF) patients is acquisition of chronic Pseudomonas (P.) aeruginosa infections. The infection rate with P. aeruginosa increases with age and by age 18 years, 80% of patients with CF in the U.S. are infected. Liposomal amikacin for inhalation (LAI; Arikayce™) is a sterile aqueous liposomal suspension consisting of amikacin sulfate encapsulated in liposomes. This formulation of amikacin maximizes the achievable dose and delivery to the lungs of infected patients when delivered via a nebulizer. Because liposome particles are small enough to penetrate and diffuse through sputum into the bacterial biofilm, they deposit drug close to the bacterial colonies (Meers, et al., 2008) (Clancy, et al., 2013), thus improving the bioavailability of amikacin at the infection site. The clinically achievable doses of amikacin in the LAI formulation can effectively increase the half-life of the drug in the lungs, and decrease the potential for systemic toxicity. LAI offers several advantages over current therapies in treating patients with CF with chronic infection caused by P. aeruginosa.

Detailed description:
Cystic fibrosis (CF) is a genetic disease resulting from mutations in a 230 kb gene on chromosome 7 known as the cystic fibrosis transmembrane conductance regulator (CFTR). Patients with CF manifest pathological changes in a variety of organs that express CFTR. The lungs are frequently affected, the sequelae being chronic infections and airway inflammation. The principal goal of treatment of patients with CF is to slow the chronic deterioration of lung function.

This study is a Phase 2 study to evaluate the longer term safety, tolerability and efficacy of 560 mg once daily dose of Arikayce™ administered for 6 cycles over 18 months. Each cycle comprises 28 days of treatment followed by 56 days off treatment.

All study patients will receive study drug by inhalation via a PARI® eFlow nebulizer. All study patients will be followed for safety, pharmacokinetics (PK), clinical, and microbiologic activity for 28 days post completion of study treatment.

The original TR02-105 study was a Phase 2a study of safety and tolerability of 28 days of daily dosing of two dose cohorts (280 mg and 560 mg) of Arikayce™ versus placebo. Study subjects were randomized to receive either study drug or placebo (1.5% NaCl) by inhalation via a PARI® eFlow nebulizer. Cohort 1 (280 mg) completed 28 days of daily dosing with Arikayce™ and 14-day post-dosing safety evaluation by the Safety Committee before initiation of enrollment in Cohort 2 (560 mg). Cohort 2 completed 28 days of daily dosing, and a 14-day post-dosing safety assessment by the Data Safety and Monitoring Board (DSMB) to evaluate safety data. All study patients were followed for safety, PK and clinical and microbiologic activity for 28 days post completion of study treatment. Details of the original study are provided at ClinicalTrials.gov ID NCT00777296.

DSMB has recommended the amendment of the main study to evaluate safety and efficacy of additional cycles of treatment with Arikayce™. All patients who were randomized in the main study, were compliant with the study protocol, and continue meeting study eligibility criteria can be consented to participate in the open-label extension to evaluate the safety, tolerability, and efficacy of 560 mg once daily dose of Arikayce™ administered for 6 cycles over 18 months. Each cycle comprises 28 days of treatment followed by 56 days off treatment.

Clinical laboratory parameters, audiology testing, clinical adverse events and pulmonary function will be evaluated for all study subjects in order to determine the longer term safety, tolerability, and efficacy of Arikayce™. Serum specimens will be collected at periodic intervals to assess PK for safety. Additionally, sputum samples will be collected to determine changes in bacterial density. Pulmonary function testing and Cystic Fibrosis Questionnaire-Revised (CFQ-R) measurements will be assessed at selected time points throughout the study. Arikace™, Arikayce™, Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and other studies evaluating amikacin liposome inhalation suspension.

Arms:
arm 1: Subjects in this cohort will receive 560 mg of Arikayce™

Interventions: intervention 1: Arikayce™
Intervention descriptions: intervention 1: Amikacin (aminoglycoside) in a liposomal formulation.

Protocol document: