Safety/Tolerability Study of Arikayce™ in Cystic Fibrosis Patients With 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 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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Arikayce™ 560 mg
* Drug: Placebo for 560 mg
* Drug: Arikayce™ 70 mg
* Drug: Arikayce™ 140 mg
* Drug: Placebo for 70 mg / 140 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Arikayce™ at 560 mg Subjects randomized 2:1 to receive Arikayce 560 mg or Placebo. | Drug: Arikayce™ 560 mg<br>* 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.<br>|
| Placebo Comparator: B<br>Matching placebo for 560 mg Subjects randomized 2:1 to receive Arikayce 560 mg or Placebo. | Drug: Placebo for 560 mg<br>* 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.<br>|
| Active Comparator: C<br>Arikayce™ at 70 mg Subjects randomized 1:1:1 to receive Arikayce 70 mg, Arikayce 140 mg or Placebo. | Drug: Arikayce™ 70 mg<br>* 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.<br>|
| Active Comparator: D<br>Arikayce™ at 140 mg Subjects randomized 1:1:1 to receive Arikayce 70 mg, Arikayce 140 mg or Placebo. | Drug: Arikayce™ 140 mg<br>* 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.<br>|
| Placebo Comparator: E<br>Matching placebo for 70 mg/140 mg Subjects randomized 1:1:1 to receive Arikayce 70 mg, Arikayce 140 mg or Placebo. | Drug: Placebo for 70 mg / 140 mg<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events | To evaluate the safety and tolerability of 28 days of daily dosing of nebulized Arikayce™, liposomal amikacin for inhalation. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Arikayce™ in Serum | Measure PK parameter (Cmax) of Arikayce in serum | Day 1, Day 14 and Day 28 | 
| Pharmacokinetics (PK) of Arikayce™ in Sputum | Measure PK parameters (sputum concentration) of Arikayce in sputum, pre- and post-dose | Day 1 post-dose, Day 14 pre- and post-dose, Day 28 pre- and post-dose | 
| Pharmacokinetics (PK) of Arikayce™ in Urine | Measure PK parameter (Ae0-24) of Arikayce in urine | Day 1, Day 14 and Day 28 | 
| Pharmacokinetics (PK) of Arikayce™ in Serum | Measure PK parameter (AUC) of Arikayce in Serum | Day 1, Day 14 and Day 28 | 
| Pulmonary Function: Pre-Dose FEV1 (%-Predicted) | Relative Change (%) from Baseline to Day 28, Day 56, Day 70, and Day 84 in Pulmonary Function | Baseline, Day 28, Day 56, Day 70 and Day 84 | 
| Density of Pseudomonas Aeruginosa in Sputum | Change (log10 CFU) from Baseline by Study Day and Treatment Arm | Day 7, Day 14, Day 21, Day 28 and Day 35 | 
| Duration of Systemic Anti-Pseudomonal Rescue Therapy |  | Through study duration, approximately 84 days | 
| CFQ-R Respiratory Scale (Relative Change % From Baseline) | 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. | Day 15, Day 28 and Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Respiratory Infections, Pulmonary Cystic Fibrosis, CFTR