Safety and Tolerability Study of 2 Dose Level of Arikayce™ in Patients With Bronchiectasis and Chronic Infection Due to Pseudomonas Aeruginosa.

Safety and Tolerability Study of 2 Dose Level of Arikayce™ in Patients With Bronchiectasis and Chronic Infection Due to Pseudomonas Aeruginosa.

A Placebo Controlled, Randomized, Parallel Cohort, Safety And Tolerability Study Of 2 Dose Levels Of Liposomal Amikacin For Inhalation (Arikayce™) In Patients With Bronchiectasis Complicated By Chronic Infection Due To Pseudomonas Aeruginosa.

This is a study to determine the safety and tolerability of 28 days of daily dosing of two doses (280 mg and 560 mg) of Arikayce™ versus placebo in patients who have bronchiectasis and chronic infection due to Pseudomonas infection.

Bronchiectasis is a chronic disorder of the major bronchi and bronchioles characterized by permanent dilation, microbial infection, a persistent inflammatory response with the release of immune mediators and microbial toxins leading to destruction. The origin of bronchiectasis varies, but the presence of microbial infection and a persistent inflammatory response is typical of the disease. The chronic nature of the infection and the associated considerable morbidity provides the rationale for using aerosolized antibiotics for the treatment of bronchiectasis patients. This is a multi-national Phase 2 study of safety and tolerability of 28 days of daily dosing with two dose levels (280 mg and 560 mg) of Arikayce™ versus placebo in subjects with bronchiectasis and chronic Pseudomonas infection. Study subjects will be randomized to receive either study drug or placebo by inhalation via a PARI eFlow® nebulizer. Each subject will complete 28 days of daily dosing. All study subjects will be followed for microbiologic activity for 14 days after completion of treatment and for safety for 28 days post completion of study treatment. The total study duration will be 56 days, with the screening visit occurring within the preceding 14 days prior to study day 1. At Day 1 (baseline), subjects will be evaluated at pre-dose and during the first 4-5 hours post-dose. Subjects will return at Week 2 (day 14) after start of treatment and at the end of Week 4 (Day 28) treatment period to determine safety and efficacy of Arikayce™. Subjects will be followed up on study Days 42 and 56 (about 2 and 4 weeks after end of treatment) for safety determination. After completion of this study, subjects will be followed up for an additional 6 months via phone contacts and records review, if hospitalized or treated for pulmonary exacerbation (under the extension protocol). 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 pharmacokinetics (PK) in subjects who consent for the PK portion of the study. Additionally, sputum samples will be collected to determine changes in bacterial density. Total Pulmonary Symptom Severity Score (PSSS) will be assessed, and respiratory quality of life will be evaluated by using the St. George's Respiratory Questionnaire (SGRQ). Arikace™,Arikayce™, Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and the other studies evaluating amikacin liposome inhalation suspension.

Bronchiectasis, Respiratory Infections, Amikacin, Respiratory Tract Diseases, Respiratory Tract Infections, Lung Diseases, Pseudomonas aeruginosa, Amikacin liposome inhalation suspension (ALIS)

Study subjects will receive Arikace™ 280 mg on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Study subjects will receive placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Study subjects will receive Arikace™ 560 mg on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Study subjects will receive placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.

Number of Subjects reporting TEAE in the Arikayce™ groups and the placebo groups during the study. The table shows the events incidents, not the number of participants.

Treatment-emergent Marked Laboratory Abnormalities up to 28 Days After Study Medication Discontinuation

Number of subjects reporting Incidence of clinically significant abnormalities in clinical values (Common Terminology Criteria for Adverse Events [CTCAE] grade >= 3) in Arikayce™ and placebo groups.

Changes in PFT from pre-dose during the study were measured on Days 1, 14, and 28. Acute tolerability of the study treatment was assessed by examining the relative (rel.) changes in FEV1 from pre-dose assessments to 0-1 hour post-dose and 2-4 hours post-dose for each time point at which post-dose spirometry was conducted.

Pre-dose, 0-1 hour post-dose and 2-4 hours post-dose on day 1, 0-1 hour post-dose and 2-4 hours post-dose on day 14, and 0-1 hour post-dose and 2-4 hours post-dose on day 28

Number of subjects with a SAE in the Arikace™ groups and the placebo group up to 28 days after study medication discontinuation. See SAE table in the safety section for details.

The change in Pseudomonas aeruginosa density from from baseline to Day 14, 28, and 42 were evaluated.Treatment differences with respect to the changes from baseline to each measured study day, defined as the log10 of the sum of all morphotypes (colony-forming units [CFU]) per gram of sputum in (log10CFU/gram [g]), was estimated for each treatment group; standard deviations accompanied the treatment differences.

Changes in the severity and intensity (frequency x severity) of individual symptoms and change in composite PSSS from baseline to Days 14, 28, 42 and 56. The Pulmonary Symptom Severity Score (PSSS) was assessed on patient's responses to the Patients Symptoms Questionnaire, which employs symptom frequency and severity scales described for the validated Memorial Symptoms Assessment Scale. Symptom severity was scored on a scale of 0 (not applicable or symptom not present) to 4 (very severe) for each of the 5 symptoms (cough, shortness of breath, sputum production [frequency and severity], fatigue, and wheezing), and a composite score (range, 0 to 20 [low score represents better outcome]) was obtained as the sum of the severity scores for each symptom.

A composite total score is derived as the sum of domain scores for symptoms, activity, and impact, with 0 as the best possible score and 100 as the worst possible score. A reduction in score of 4 points is generally recognized as a clinically meaningful improvement in quality of life. This analysis compared the changes from Day 1 (prior to first dosing) to Days 14, 28, 42, and 56.

Inclusion Criteria: Male or female study subjects≥ 18 years of age Confirmed diagnosis of multi-focal bronchiectasis in two or more lung segments by HRCT of the chest History of chronic infection with P. aeruginosa Confirmation of infection with P. aeruginosa at screening SaO2 ≥ 90% at Screening while breathing room air Ability to comply with study medication use, study visits, and study procedures as judged by the investigator Ability to produce at least 0.5 grams sputum or be willing to undergo an induction to produce sputum for clinical evaluation Key Exclusion Criteria: Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted at Screening Patients with hemoptysis of ≥60 mL within 4 weeks prior to screening Bronchiectasis due to cystic fibrosis (CF), bronchopulmonary Aspergillus, aspiration of foreign body, or secondary to lung compression from tumors History of non-tuberculous mycobacterial and/or Aspergillus infection requiring treatment or treated within 2 years prior to screening Pulmonary tuberculosis requiring treatment or treated within two years prior to screening History of Lung transplantation Use of any inhalation or systemic antibiotics (IV antibiotics, or oral antibiotics) within 4 weeks prior to Study Day 1 Evidence of biliary cirrhosis with portal hypertension Smoking tobacco or any substance within 6 months prior to screening, and throughout the study History of alcohol, medication, or illicit drug abuse within the 1 year prior to screening