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

Phase 3

Completed

Conditions: Cystic Fibrosis
Lung Infection
Pseudomonas Aeruginosa

Interventions: Drug: Placebo three times daily (TID)
Drug: AZLI 75 mg three times daily (TID)

Registration Number: NCT00712166

Lead Sponsor: Gilead Sciences

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), mild lung disease (forced expiratory volume in 1 second \[FEV1\] \>75% predicted, and Pseudomonas aeruginosa (PA) infection.

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 three times a day using the PARI eFlow® electronic nebulizer, in CF patients with PA and mild lung disease.

In this study, participant eligibility was assessed at a screening visit that occurred up to 14 days prior to the baseline visit (Day 0). Those participants who met eligibility criteria at Day 0 were randomized and began a 28-day course of blinded study treatment (AZLI 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 the trial drug (Day 42).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 160

Inclusion Criteria

Participants ≥ 6 years of age
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 ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test
- Two well characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
- Abnormal nasal potential difference
PA present in expectorated sputum or throat swab culture at Visit 1 OR documented PA in 2 expectorated sputum or throat swab cultures within the 12 months prior to Visit 1 (one of the previous PA positive cultures must have been no more than 3 months prior to Visit 1)
FEV1 > 75% predicted at Visit 1
Participants must have exhibited two or more of the following chronic and/or intermittent CF symptoms, for a minimum of 28 days prior to randomization and with no worsening of symptoms within 7 days prior to randomization:
- Chest congestion
- Daily cough
- Productive cough
- Wheezing
- Trouble breathing
- Nocturnal wakening due to coughing
Participants (and parent/guardian as required) had to be able to provide written informed consent/assent prior to any study related procedures
Females of childbearing potential had to have a negative urine pregnancy test at Visit 1
Ability to perform reproducible pulmonary function tests
In the opinion of the Investigator, the participant did not require immediate antipseudomonal antibiotic intervention to treat an impending exacerbation, and the participant's condition was stable enough to enroll in the study

Exclusion Criteria

Administration of any investigational drug or device within 28 days prior to Visit 1 or within 6 half-lives of the investigational drug (whichever was longer)
Administration of any IV, oral, or inhaled antipseudomonal antibiotic within 28 days prior to Visit 1
Known local or systemic hypersensitivity to monobactam antibiotics
Inability to tolerate short-acting bronchodilator (BD) use at least TID
Changes in or initiation of chronic azithromycin treatment within 28 days prior to Visit 1
Changes in or initiation of chronic hypertonic saline treatment within 28 days prior to Visit 1
Changes in or initiation of dornase alfa within 28 days prior to Visit 1
Changes in antimicrobial, BD, 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
History of participation (enrollment) in any prior clinical studies with AZLI
A chest radiograph at Visit 1 (or within the previous 180 days of Visit 1), with abnormalities indicating a significant acute finding (e.g., lobar infiltrate and atelectasis, pneumothorax, or pleural effusion); a chest radiograph obtained and interpreted between Visits 1 and 2 was also acceptable for determining eligibility
Positive urine pregnancy test at Visit 1; all women of childbearing potential were to be tested
Females of childbearing potential who were lactating or were not (in the opinion of the investigator) practicing an acceptable method of birth control; female participants who utilized hormonal contraceptives as their birth control method must have used the same method for at least 3 months before study dosing
Participant was being assessed at Visit 1 by the investigator for an acute change in respiratory symptoms
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo three times daily (TID)	Placebo three times daily (TID)	-
AZLI 75 mg three times daily (TID)	AZLI 75 mg three times daily (TID)	-

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28	Day 0 to Day 28	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in CFQ-R RSS Score at Day 14	Day 0 to Day 14	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Change From Baseline in CFQ-R RSS Score at Day 42	Day 0 to Day 42	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0, 14, 28, and 42. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from Day 0 (baseline), assessed with the CFQ-R RSS (score range: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R RSS and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Change From Baseline in CFQ-R Physical Functioning Domain Score	Day 0 to Day 28	The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Days 0 (baseline), 14, 28, and 42 (the last study visit). The endpoint was change from baseline in the physical functioning domain (e.g., ability to walk and engage in physical activities) of the CFQ-R at Day 28 (range of scores: 0-100; higher scores indicating fewer symptoms, higher health-related quality of life, or better functioning). Baseline CFQ-R physical functioning domain score and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study	Day 0 to Day 42	The number of participants requiring additional antipseudomonal antibiotics (oral, intravenous \[IV\], or by inhalation), the time to use of these antibiotics, and the reasons for use was recorded. A binary variable was defined to indicate whether the participants needed any antipseudomonal antibiotics that were non-study drug via the oral, IV, or inhalation route between Day 0 (Baseline Visit) and Day 42 (Visit 5). Fisher's Exact Test was implemented on the intent-to-treat (ITT) and per protocol analysis sets to detect treatment effects on need for additional antipseudomonal antibiotics.
Number of Participants Hospitalized During Study	Day 0 to Day 42	Hospitalization was defined as any hospital admission lasting for more than 1 calendar day that had been recorded as a serious adverse event (SAE) on the electronic case report form (eCRF). Binary variables were defined to indicate whether participants experienced any hospitalization. Number of hospitalizations was summarized by treatment group.
Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28	Day 0 to Day 28	Sputum samples were collected at all study visits for quantitative and qualitative culture for PA. Sputum PA density was quantified by logarithm transformation of the CFU value with base 10. Change from baseline in sputum PA density was calculated as the difference between the log10 CFU values at Day 28 (Visit 4) and the baseline value. Missing data was not imputed. Baseline log10 CFU and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.
Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Day 0 to Day 28	Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested by the ANCOVA model using the ITT analysis set. Baseline FEV1 percent predicted and age group (\<18 vs. \>=18 years) were included as covariates in the analysis.

Trial Locations

Locations (39): Children's Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Penn Presbyterian Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
Drexel University College of Medicine, Pulmonary Associates
🇺🇸
Philadelphia, Pennsylvania, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
University of Michigan Health System
🇺🇸
Ann Arbor, Michigan, United States
University Medical Center
🇺🇸
Tucson, Arizona, United States
University of Arkansas for Medical Sciences, Division of Pulmonary and Critical Care Medicine
🇺🇸
Little Rock, Arkansas, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Kaiser Permanente
🇺🇸
Oakland, California, United States
Indiana University, Outpatient Clinical Research Facility
🇺🇸
Indianapolis, Indiana, United States
James Whitcomb Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
The Children's Hospital of Michigan, Detroit Medical Center
🇺🇸
Detroit, Michigan, United States
The Minnesota CF Center, University of Minnesota Medical Center
🇺🇸
Minneapolis, Minnesota, United States
Children's Lung Specialists
🇺🇸
Las Vegas, Nevada, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Santiago Reyes, MD
🇺🇸
Oklahoma City, Oklahoma, United States
Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Primary Children's Medical Center
🇺🇸
Salt Lake City, Utah, United States
Children's Hospital and Regional Medical Center
🇺🇸
Seattle, Washington, United States
Phoenix Children's Hospital
🇺🇸
Phoenix, Arizona, United States
The Children's Hospital
🇺🇸
Aurora, Colorado, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Children's Hospital, Boston
🇺🇸
Boston, Massachusetts, United States
Nemours Children's Clinic
🇺🇸
Orlando, Florida, United States
Tufts Medical Center, Pediatric Pulmonary Clinic
🇺🇸
Boston, Massachusetts, United States
The Lung & Cystic Fibrosis Center, University of Buffalo Pediatric Associates, Inc., Women & Children's Hospital of Buffalo
🇺🇸
Buffalo, New York, United States
Albany Medical College
🇺🇸
Albany, New York, United States
SUNY Upstate Medical University
🇺🇸
Syracuse, New York, United States
Long Island Jewish Medical Center
🇺🇸
New Hyde Park, New York, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Toledo Children's Hospital/Toledo Hospital, Cystic Fibrosis Research Center
🇺🇸
Toledo, Ohio, United States
Department of Respiratory Medicine, The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Penn State Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
St. Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Department of Respiratory Medicine, Westmead Hospital
🇦🇺
Westmead, New South Wales, Australia
Respiratory Medicine, Royal Children's Hospital
🇦🇺
Herston, Queensland, Australia
The Prince Charles Hospital, Adult Cystic Fibrosis Centre
🇦🇺
Chermside, Queensland, Australia
Child and Adolescent Health Services, Princess Margaret Hospital
🇦🇺
Perth, Western Australia, Australia
Centre de Recherche du CHUM
🇨🇦
Montreal, Quebec, Canada