International Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Cystic Fibrosis Patients With P. Aeruginosa

Study Overview
=================
Brief Summary
-----------------
The purpose of this study was to evaluate the safety and efficacy of a 28-day course of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF) and lung infection due to Pseudomonas aeruginosa (PA).

Detailed Description
-----------------
CF patients often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by a bacteria called Pseudomonas aeruginosa (PA). Treatment with antibiotics can stop or slow down the growth of the bacteria. The antibiotics may be given by mouth, intravenously (IV), or by inhalation as a mist. The purpose of this study was to evaluate the safety and efficacy of AZLI, an investigational formulation of the antibiotic aztreonam and administered TID using the PARI eFlow® electronic nebulizer, in CF patients with PA. In this study, participant eligibility was assessed at a screening visit 7 to 14 days prior to the baseline visit (Day 0). Those participants who continued to meet eligibility criteria at Day 0 were randomized and began a 28-day course of blinded study treatment (AZLI TID or placebo TID). Participants returned for clinic visits at Day 14, an end of treatment visit at Day 28, and a follow-up visit 14 days after the last dose of study drug (Day 42).

Official Title
-----------------
A Phase 3, Double-Blind, Multicenter, Multinational, Randomized, Placebo-Controlled Trial Evaluating Aztreonam Lysinate for Inhalation in Cystic Fibrosis Patients With Pulmonary Pseudomonas Aeruginosa (AIR-CF1)

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Drug: AZLI 75 mg three times a day (TID)
* Drug: Placebo three times a day (TID)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documentation of CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria: Sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT); Two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or Abnormal nasal potential difference. PA present in expectorated sputum or throat swab culture at Screening. FEV1 between (and including) 25% and 75% predicted at Screening. Negative pregnancy test at Screening. Ability to perform reproducible pulmonary function tests. Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening. Ability to provide written informed consent. Exclusion Criteria: Administration of antipseudomonal antibiotics by inhalation, IV, or oral routes (including azithromycin) within 14 days of Screening. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone/day or 20 mg prednisone every other day. History of sputum or throat swab culture yielding Burkholderia cepacia in the previous 2 years. History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night. Administration of any investigational drug or use of any investigational device within 28 days of Screening and within 6 half-lives of the investigational drug (whichever was longer). Known local or systemic hypersensitivity to monobactam antibiotics. Inability to tolerate short-acting bronchodilator use at least three times daily. Changes in protocol-permitted antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days prior to Screening or between Screening and the next visit. Changes in physiotherapy technique or schedule within 7 days prior to Screening or between Screening and the next visit. History of lung transplantation. A chest x-ray indicating abnormal findings at Screening or within the previous 90 days. Abnormal renal or hepatic function at Screening. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would have interfered with participant treatment, assessment, or compliance with the protocol. Use of aerosolized hypertonic saline (except for sputum induction) during the 14 days preceding Visit 1.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo three times a day (TID)<br> | Drug: Placebo three times a day (TID)<br> <br> |
| Experimental: AZLI 75 mg three times a day (TID)<br> | Drug: AZLI 75 mg three times a day (TID)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CFQ-R Respiratory Symptoms Scale (RSS) Score | The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R respiratory symptoms scale (RSS; range of scores: 0-100; higher scores indicate fewer symptoms). | Day 0 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CFQ-R RSS Score | The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms). | Day 0 to Day 14 | 
| Change in CFQ-R RSS Score | The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms). | Day 0 to Day 42 | 
| Percent Change in FEV1 (L) | Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. The percent change from baseline in forced expiratory volume (liters) in one second (FEV1) was determined at Day 28. | Day 0 to Day 28 | 
| Change From Baseline in Pseudomonas Aeruginosa (PA) Log10 Colony Forming Units (CFU) Per Gram of Sputum | Sputum samples were collected at all participant visits of the study for analysis of microbiology endpoints. Sputum samples were processed for qualitative and quantitative culture of PA (each morphotype). Due to the skewness of the distribution of CFU data, the data were transformed using the base 10 logarithm, in an attempt to normalize the data and allow for parametric tests, before calculating changes. To account for zero values, 1 was added to each CFU measurement before being transformed. Any CFU data values where PA was not isolated from a valid culture were set to zero. | Day 0 to Day 28 | 
| Number of Participants Receiving Intravenous (IV) or Inhaled Antipseudomonal Antibiotics Other Than Trial Drug | Use of IV and inhaled antipseudomonal antibiotics was compiled from data recorded on the Concomitant Medications eCRF. | Day 0 to Day 42 | 
| Number of Participants Hospitalized at Least Once Between Day 0 and Day 42 | Details of all hospitalizations, including the dates of admission and discharge, were recorded on the SAE eCRF. | Day 0 to Day 42 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cystic Fibrosis, Pseudomonas aeruginosa, Pulmonary Cystic Fibrosis