Phase 3 Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy Regimen for the Treatment of Chronic Pseudomonas Aeruginosa Infection in Patients With CF

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and efficacy of a CAT regimen with aztreonam for inhalation solution (AZLI) and tobramycin inhalation solution (TIS) in adult and pediatric subjects with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection. Participants will be enrolled in a 28 day TIS run-in phase, and will be eligible for randomization in the comparative phase if they have not received non-study oral antibiotics for a respiratory event, or IV or inhaled antibiotics for any indication between Visits 2 and 3, have not developed a condition requiring hospitalization or other change in clinical status which, in the opinion of the investigator would preclude their ability to continue in the study, and have demonstrated at least 50% TIS compliance. Participants enrolled in the comparative phase will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI or placebo for 28 days followed by TIS for 28 days.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy (CAT) Regimen of Inhaled Antibiotics for the Treatment of Chronic Pulmonary Pseudomonas Aeruginosa Infection in Subjects With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: AZLI
* Drug: Placebo to match AZLI
* Drug: Tobramycin inhalation solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CF Presence of PA in 2 lower respiratory tract cultures in the 12 months prior to screening Forced expiratory volume (FEV)1 ≥ 25 and ≤ 75% predicted History of 1 hospitalization or 1 course of IV antibiotics for an acute respiratory exacerbation in the 12 months prior to screening Exclusion Criteria: Concurrent use of oral, IV or inhaled antibiotics at enrollment Concurrent hospitalization at enrollment History of local or systemic hypersensitivity to monobactams or aminoglycoside antibiotics or history of aminoglycoside antibiotic associated toxicity

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AZLI<br>Participants will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI for 28 days followed by TIS for 28 days. | Drug: AZLI<br>* Aztreonam for Inhalation Solution (AZLI) 75 mg 3 times daily combined with diluent administered using an eFlow nebulizer<br>* Other names: Cayston®;Drug: Tobramycin inhalation solution<br>* Tobramycin inhalation solution (TIS) 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor<br>* Other names: TOBI®;|
| Placebo Comparator: Placebo<br>Participants will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS for 28 days. | Drug: Placebo to match AZLI<br>* Placebo to match AZLI 3 times daily combined with diluent administered using an eFlow nebulizer<br>Drug: Tobramycin inhalation solution<br>* Tobramycin inhalation solution (TIS) 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor<br>* Other names: TOBI®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24 | PDEs were characterized by a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of non-study IV or inhaled antibiotics and be verified by a blinded independent adjudication committee. | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex and body composition. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction. | Comparative Phase: Baseline and Weeks 4, 12 and 20 | 
| Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs |  | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | 
| Time to First Protocol-defined Pulmonary Exacerbation | The time to first protocol-defined pulmonary exacerbation was calculated using the Kaplan-Meier method. | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | 
| Rate of Hospitalizations for a Respiratory Event | The rate of hospitalizations for a respiratory event per participant year was calculated using negative binomial regression analysis. | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | 
| Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction. | Comparative Phase: Baseline and Weeks 4, 12 and 20 |