Safety/Tolerability Study of Arikayce™ in Cystic Fibrosis Patients With Chronic Infection Due to Pseudomonas Aeruginosa

Safety/Tolerability Study of Arikayce™ in Cystic Fibrosis Patients With Chronic Infection Due to Pseudomonas Aeruginosa

Phase 1b/2a Multidose Safety and Tolerability Study of Liposomal Amikacin for Inhalation (Arikayce™) in Cystic Fibrosis Patient With Chronic Infections Due to Pseudomonas Aeruginosa.

This is a study to determine the safety and tolerability of 28 days of daily dosing of 560 mg of Arikayce™ versus placebo and daily dosing of 70 mg and 140 mg of Arikayce™ versus placebo in patients who have Cystic fibrosis (CF) and chronic infection due to pseudomonas aeruginosa.

CF is a gentic 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 or organs that express CFTR. The lungs are frequently affected, the sequelae being chronic infections and airway inflammation. The principal goal of both treatment of subjects with CF is to slow the chronic deterioration of lung function. Study subjects will be randomized to receive either study drug or placebo (1.5% NaCl) by inhalation via a PARI eFlow nebulizer. Each subject will complete 28 days of daily dosing. All study patients will be followed for safety, pharmacokinetics, clinical and microbiologic activity for 56 days post completion of study treatment. For the two lower doses (70 mg and 140 mg): patients received drug for 28 days, followed by a 28 day safety evaluation. For 560 mg: patients received drug for 28 days, followed by a 56 day safety evaluation. The total study period will be up to 84 days, with screening visit occurring within the preceding 14 days prior to study day 1. Patients will be clinically evaluated during the first 48 hours post first study dose and weekly for the 28 day treatment period and during the follow up visits at study days 35, 42, 49, 56, 70 and 85 days to determine safety and 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 Arikayce™ 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. An exploratory evaluation of a Cystic Fibrosis Symptom Diary (CFSD) will also be implemented. 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 liposomal inhalation suspension.

Matching placebo for 70 mg/140 mg Subjects randomized 1:1:1 to receive Arikayce 70 mg, Arikayce 140 mg or Placebo.

Arikayce™ at 560 mg Subjects will be randomly assigned to study drug dose of of Arikayce™ or placebo in accordance with a code provided by the Sponsor/CRO. Randomization will be made in a 2:1 allocation between Arikayce™ and placebo. They will be blinded whether they receive Arikayce™ or Placebo Study subjects will receive Arikayce™ or placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Matching placebo Subjects will be randomly assigned to study drug dose of of Arikayce™ or placebo in accordance with a code provided by the Sponsor/CRO. Randomization will be made in a 2:1 allocation between Arikayce™ and placebo. They will be blinded whether they receive Arikayce™ or Placebo Study subjects will receive Arikayce™ or placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Subjects will be randomly assigned to study drug dose of of Arikayce™ or placebo in accordance with a code provided by the Sponsor/CRO. Randomization will be made in a 1:1:1 allocation between Arikayce™ and placebo. They will be blinded whether they receive Arikayce™ or Placebo Study subjects will receive Arikayce™ or placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Subjects will be randomly assigned to study drug dose of of Arikayce™ or placebo in accordance with a code provided by the Sponsor/CRO. Randomization will be made in a 1:1:1 allocation between Arikayce™ and placebo. They will be blinded whether they receive Arikayce™ or Placebo Study subjects will receive Arikayce™ or placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Matching placebo Subjects will be randomly assigned to study drug dose of of Arikayce™ or placebo in accordance with a code provided by the Sponsor/CRO. Randomization will be made in a 1:1:1 allocation between Arikayce™ and placebo. They will be blinded whether they receive Arikayce™ or Placebo Study subjects will receive Arikayce™ or placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

To evaluate the safety and tolerability of 28 days of daily dosing of nebulized Arikayce™, liposomal amikacin for inhalation.

Quality of Life was measured by the absolute change from baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory scale. Disease specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms in patients with a diagnosis of cystic fibrosis. Scores range from 0 to 100, with higher scores indicating better health. Scores for each Health Related Quality of Life (HRQoL) domain; after recoding, each item is summed to generate a domain score and standardized.

Key Inclusion Criteria: Male or female study subjects must be adults (≥ 6 years of age) Confirmed diagnosis of CF History of chronic infection with P.aeruginosa FEV1 ≥40% of predicted at Screening Ability to comply with study medication use, study visits and procedures Ability to produce 0.5 grams of sputum Key Exclusion Criteria: Administration of any investigational drug within 8 weeks to Study Day 1 Emergency room visit or hospitalization for CF or respiratory-related illness within 4 weeks prior to screening History of alcohol, medication or illicit drug abuse within 1 yr. to screening History of lung transplantation Female of childbearing potential who are not practicing an acceptable method of birth control or who are lactating Positive Pregnancy test Use of any anti-pseudomonal antibiotics within 28 days prior to Study Day 1 Initiation of chronic therapy within 28 days prior to Study Day 1 History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years prior to screening History of mycobacterial and/or Aspergillus infection requiring treatment within 2 years prior to screening History of biliary cirrhosis with portal hypertension, or splenomegaly

Okusanya OO, Bhavnani SM, Hammel JP, Forrest A, Bulik CC, Ambrose PG, Gupta R. Evaluation of the pharmacokinetics and pharmacodynamics of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infections using data from two phase 2 clinical studies. Antimicrob Agents Chemother. 2014 Sep;58(9):5005-15. doi: 10.1128/AAC.02421-13. Epub 2014 Mar 31.

Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH, Lymp J, Minic P, Quittner AL, Rubenstein RC, Young KR, Saiman L, Burns JL, Govan JR, Ramsey B, Gupta R; Arikace Study Group. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax. 2013 Sep;68(9):818-25. doi: 10.1136/thoraxjnl-2012-202230. Epub 2013 Jun 8.