Aztreonam for Inhalation Solution vs Tobramycin Inhalation Solution in Patients With Cystic Fibrosis & Pseudomonas Aeruginosa

Study Overview
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Brief Summary
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The purpose of this study was to assess the comparative safety and effectiveness of aztreonam for inhalation solution versus tobramycin inhalation solution in adult and pediatric patients with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection.

Detailed Description
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Number of Subjects Planned: Approximately 240 randomized patients Target Population: CF patients >= 6 years of age with stable pulmonary disease, who at study entry had a recent positive sputum culture for PA and had been previously treated with aerosolized antibiotics without demonstration of drug intolerance. The randomized phase of this study, used for hypotheses testing, enrolled participants from both the United States (US) and EU. An open-label, single-arm extension was available for participants in the EU who completed at least one course of AZLI or TIS during the randomized portion of the study. These participants were eligible to receive 3 additional cycles of AZLI in a 28-day, intermittent, repeating treatment regimen. Results of the extension phase will be available the first quarter (Q1) of 2012. Randomized Phase Study Design (US and EU): This was an open-label, multicenter, randomized, parallel group study. The study design consisted of 2 treatment arms of 28-day, intermittent, repeating treatment regimens: aztreonam for inhalation solution (AZLI) or tobramycin inhalation solution (TIS). The total study period was 26 weeks. The study schedule included 9 visits - Screening, Baseline, Day 14, Day 28, followed by visits every 28 days through the end of the study.

Official Title
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An Open-Label, Randomized, Phase 3 Trial to Evaluate the Efficacy and Safety of Aztreonam for Inhalation Solution (AZLI) Versus Tobramycin Inhalation Solution (TIS) in an Intermittent Aerosolized Antibiotic Regimen in Subjects With Cystic Fibrosis Followed by an Open-Label, Single Arm Extension (European Union [EU] Only)

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Aztreonam for Inhalation Solution (AZLI)
* Drug: Tobramycin Inhalation Solution (TIS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 6 years and older Subjects with CF as diagnosed by one of the following: documented sweat chloride >= 60 mEq/L by quantitative pilocarpine iontophoresis test, or documented sweat sodium >= 60 mmol/L, or 2 well characterized genetic mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, or abnormal nasal potential difference with accompanying symptoms characteristic of CF Documented PA in an expectorated sputum or throat swab culture within 3 months prior to Visit 1 or at Visit 1 Subjects must be able to provide written informed consent/assent prior to any study related procedures; parent/guardian must be able to give written informed consent as necessary prior to any study related procedure Subjects must have received previous treatment with aerosolized antibiotics without demonstration of drug intolerance FEV1 <= 75% predicted at Visit 1 Ability to perform reproducible pulmonary function tests Chest radiograph at Visit 1 without significant acute findings (eg, infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax); or chest radiograph or magnetic resonance image (MRI) obtained within the 180 days prior to Visit 1 without acute findings and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) are allowed Exclusion Criteria: Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day History of sputum or throat swab culture yielding B. cepacia in the previous 2 years Current requirement for daily continuous oxygen supplementation or requirement for more than 2 L/minute at night Administration of any investigational drug or device within 28 days of Visit 1 or within 6 half-lives of the investigational drug (whichever is longer) Known local or systemic hypersensitivity to monobactam antibiotics Known allergies/intolerance to tobramycin Inability to tolerate inhalation of a short acting beta agonist Changes in or initiation of chronic azithromycin treatment within 28 days prior to Visit 1 Administration of antipseudomonal antibiotics by inhalation, intravenous or oral routes within the 14 days prior to Randomization/Visit 2 Changes in antimicrobial, bronchodilator (BD), dornase alfa, or corticosteroid medications within 7 days prior to Visit 1 Changes in physiotherapy technique or schedule within 7 days prior to Visit 1 History of lung transplantation Abnormal renal or hepatic function or serum chemistry at Visit 1, defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 5 times upper limit of normal range (ULN) or creatinine > 2 times ULN Positive pregnancy test at Visit 1; all women of childbearing potential will be tested Female of childbearing potential who is lactating or is not (in the opinion of the investigator) practicing an acceptable method of birth control; female subjects who utilize hormonal contraceptives as one of their birth control methods must have used the same method for at least 3 months before study dosing Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with patient treatment, assessment, or compliance with the protocol

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZLI 75 mg 3 times a day (TID)<br> | Drug: Aztreonam for Inhalation Solution (AZLI)<br>* Aztreonam for inhalation solution (75 mg) was administered 3 times a day (TID) for 28 days for each treatment cycle via the PARI eFlow electronic nebulizer.<br>* Other names: inhaled antibiotic;|
| Active Comparator: TIS 300 mg 2 times a day (BID)<br> | Drug: Tobramycin Inhalation Solution (TIS)<br>* Tobramycin inhalation solution (300 mg) was administered 2 times a day (BID) for 28 days for each treatment cycle via the PARI LC Plus nebulizer with compressor or via another nebulizer compatible with country-specified labeling.<br>* Other names: inhaled antibiotic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28 | Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an analysis of covariance (ANCOVA) model-based method. | Baseline and end of treatment Course 1 (Day 28) | 
| Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses | Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by mixed-effect model repeated measures (MMRM) analysis using the ITT population analysis set. | Baseline, and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | Spirometry was performed according to ATS guidelines. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an ANCOVA model-based method, using the population of participants with prior inhaled tobramycin use of >= 84 days in the previous 12 months. | Baseline and end of treatment Course 1 (Day 28) | 
| Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by MMRM analysis using the population of participants with prior inhaled tobramycin use of >=84 days in the previous 12 months. | Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20) | 
| Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events | IV antipseudomonal antibiotic use for a respiratory event was determined through the adjudication of events by a sponsor-independent, blinded review committee. Use was compiled from data recorded on the concomitant medications electronic case report form (eCRF) and compared to reported adverse events (AEs) to determine use for a respiratory event. The time to IV antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first IV antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored. | Day 0 to Day 168 (end of study) | 
| Time to First Respiratory Hospitalization | This endpoint was determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed all hospitalizations and determined which were related to respiratory events. Details of all hospitalizations, including the dates of admission and discharge, were recorded on the serious adverse event (SAE) eCRF. Time to first respiratory hospitalization was the number of days from baseline (Visit 2) to the date of first respiratory hospitalization or the date of study completion (last visit) /or early withdrawal if censored. | Day 0 to Day 168 (end of study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aztreonam lysine, tobramycin inhalation solution, tobramycin nebuliser solution, cystic fibrosis, pseudomonas aeruginosa, lung infection, CFQ-R, inhaled antibiotic