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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Bronchiectasis

Intervention / Treatment
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* Drug: 280 mg Arikayce™
* Drug: Matching Placebo for Cohort 1
* Drug: 560 mg Arikayce™
* Drug: Matching Placebo for Cohort 2


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - 280 mg Arikayce™<br>Subjects in this arm of the cohort 1 will receive 280 mg of Arikayce™ | Drug: 280 mg Arikayce™<br>* Study subjects will receive Arikace™ 280 mg on Days 1 through Day 28. Drug is administered once a day via a nebulizer.<br>* Other names: liposomal amikacin for inhalation;|
| Placebo Comparator: Cohort 1 - Placebo<br>Subjects in this arm of the cohort 1 will receive matching placebo. | Drug: Matching Placebo for Cohort 1<br>* Study subjects will receive placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.<br>|
| Experimental: Cohort 2 - 560 mg Arikayce™<br>Subjects in this arm of the cohort 2 will receive 560 mg of Arikayce™ | Drug: 560 mg Arikayce™<br>* Study subjects will receive Arikace™ 560 mg on Days 1 through Day 28. Drug is administered once a day via a nebulizer.<br>* Other names: liposomal amikacin for inhalation;|
| Placebo Comparator: Cohort 2 - Placebo<br>Subjects in this arm of the cohort 2 will receive matching placebo | Drug: Matching Placebo for Cohort 2<br>* Study subjects will receive placebo on Days 1 through Day 28. Drug is administered once a day via a nebulizer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Treatment-emergent AEs (TEAEs) up to End of Treatment | 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. | Day 1 through 56. | 
| 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. | Day 1 through 56. | 
| Treatment-emergent Pulmonary Function Test (PFT) for Acute Tolerability Assessment | 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 | 
| Treatment-emergent PFT Abnormalities up to the End of Study | Number of Subjects with Decrease of >= 15% in FEV1 (L) from Pre- to Post-dose by Study Day | Day 1, Day 14 and Day 28 | 
| Number of Subjects With an Adverse Event Leading to Permanent Discontinuation of Study Medication |  | Screening to Day 56 | 
| Serious Adverse Events up to 28 Days After Study Medication Discontinuation | 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. | Screening to Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Log10CFU Per Gram (Density) of Pseudomonas Aeruginosa in Sputum. | 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. | Baseline to Day 14, Day 28 and Day 42. | 
| Total Pulmonary Symptom Severity Score (PSSS) | 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. | Baseline to Day 14, Day 28, Day 42 and Day 56. | 
| To Evaluate Change in St. George's Respiratory Questionnaire Measurements | 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. | Day 1 to Day 14, Day 28, Day 42 and Day 56. | 
| To Evaluate the Use of Systemic Antipseudomonal Rescue Therapy |  | Screening to Day 56. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchiectasis, Respiratory Infections, Amikacin, Respiratory Tract Diseases, Respiratory Tract Infections, Lung Diseases, Pseudomonas aeruginosa, Amikacin liposome inhalation suspension (ALIS)