Cystic Fibrosis Clinical Trial
Official title:
Phase 2a Multidose Safety and Tolerability Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKACE™) In Cystic Fibrosis Patients With Chronic Infections Due To Pseudomonas Aeruginosa.
A major factor in the respiratory health of cystic fibrosis (CF) subjects is acquisition of chronic Pseudomonas aeruginosa infections. The infection rate with P. aeruginosa increases with age and by age 18 years, 80% of CF subjects in the U.S. are infected. Liposomal Amikacin for Inhalation (Arikace™) 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 subjects infected via a nebulizer. Because liposome particles are small enough to penetrate and diffuse through sputum into the bacterial biofilm, they deposit drug in close proximity to the bacterial colonies, 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 CF subjects with chronic infection caused by P. aeruginosa.
Cystic fibrosis is a genetic disease resulting from mutations in a 230 kb gene on chromosome
7 known as the cystic fibrosis transmembrane conductance regulator (CFTR). Study subjects
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 subjects with CF is to slow the chronic deterioration of lung
function.
This is a Phase 2a study of safety, and tolerability of 28 days of daily dosing of two dose
(280 mg, and 560 mg) cohorts of Arikace™ versus placebo. Study subjects will be randomized to
receive either study drug or placebo (1.5% NaCl) by inhalation via a PARI eFlow® nebulizer.
Cohort 1 (280mg) will complete 28 days of daily dosing with Arikace™ and 14 day post dosing
safety evaluation by the Safety Committee (DSMB) before initiation of enrollment in Cohort 2
(560mg). Cohort 2 will complete 28 days of daily dosing, and a 14 day post dosing safety
assessment by the DSMB to evaluate safety data. All study patients will be followed for
safety, pharmacokinetics, clinical, and microbiologic activity for 28 days post completion of
study treatment.
The total study period will be up to 56 days, with screening visit occurring within the
preceding 14 days prior to randomization. Patients will be clinically evaluated during the
first 48 hours post-randomization, and weekly for the 28 days treatment period, and during
the follow up visits at study days 35, 42, 49, and 56 days to determine safety, tolerability,
pharmacokinetics (PK), and clinical, and microbiologic activity.
Clinical laboratory parameters, audiology testing, clinical adverse events, and pulmonary
function will be evaluated for all study subjects in order to determine the qualitative and
quantitative safety and tolerability of Arikace™ compared to Placebo. Serum, urine, and
sputum specimens will be collected at periodic intervals to assess PK. Additionally; sputum
samples will be collected to determine changes in bacterial density. Pulmonary function
testing and CFQ-R measurements will be assessed at selected time points throughout the study.
DSMB has recommended the amendment of the main study to evaluate safety and efficacy of
additional cycles of treatment with Arikace™. 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 Arikace™ administered for six cycles
over eighteen months. Each cycle will comprise of 28 days of treatment followed by 56 days
off treatment. The total extension period will be up to 518 days (74 weeks, about 18 months).
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 Arikace™. 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 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) are all the
same may be used interchangeably throughout the study and other studies evaluating amikacin
liposome inhalation suspension.
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