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

Cystic Fibrosis Clinical Trial

— AIR-CF2  

Official title:

A Phase 3, Double-Blind, Multicenter, Randomized, Placebo-Controlled Trial With Aztreonam Lysinate for Inhalation in Cystic Fibrosis Patients With Pulmonary P. Aeruginosa Requiring Frequent Antibiotics (AIR-CF2)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00104520
• Other study ID #: CP-AI-005
• Status: Completed
• Phase: Phase 3
• First received: March 1, 2005
• Last updated: February 16, 2011
• Start date: February 2005
• Est. completion date: September 2006

Study information

• Verified date: September 2010
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to evaluate the safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF) and lung infection due to Pseudomonas aeruginosa (PA).

Description:

Patients with CF often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by a bacteria called 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 aztreonam for inhalation solution (AZLI), an investigational formulation of the antibiotic administered using the eFlow® Electronic Nebulizer by PARI GmbH, in CF patients with PA.

In this study, participants were screened for eligibility at Visit 1 (Day -42) and returned to the center for Visit 2 after a 14-day evaluation period. At Visit 2 (Day -28), participants began a 28-day course of open-label Tobramycin Inhalation Solution (TIS). At Visit 3 (Day 0), following completion of the 28-day course of TIS, participants began randomized, blinded treatment with either AZLI twice a day (BID) or three times a day (TID) or placebo BID or TID, and continued treatment for a total of 28 days, with a clinic visit at Day 14 (Visit 4) and at the end of treatment (Visit 5 [Day 28]). Participants returned for visits every 2 weeks for 8 weeks after the end of the blinded treatment (Visits 6 to 9 [Days 42 to 84]).

Two hundred and forty-seven participants were treated in the TIS phase of this study. Two hundred and eleven subjects completed the TIS phase and were treated in the placebo-controlled phase with study drug (AZLI or placebo).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 211
• Est. completion date: September 2006
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years and older

Eligibility

Inclusion Criteria:

• CF as diagnosed by:

1. Documented sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test; or

2. Two well-characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or

3. Abnormal nasal potential difference with accompanying symptoms characteristic of CF.

• PA present in expectorated sputum or throat swab culture at Screening.

• Participants must have received three or more courses of TIS within the previous 12 months.

• Participants on chronic azithromycin must have had no change in regimen in the previous 3 months and must have had a need for TIS and/or additional antipseudomonal therapy since initiation of azithromycin.

• Forced expiratory volume in 1 second (FEV1) between (and including) 25% and 75% predicted at Screening.

• Ability to perform reproducible pulmonary function tests.

• Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening.

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 culture swab yielding Burkholderia cepacia in the past 2 years.

• History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night.

• Administration of any investigational drug or device within 28 days of Screening (Visit 1) or within 6 half-lives of the investigational drug (whichever was longer).

• Known local or systemic hypersensitivity to monobactam antibiotics.

• Inability to tolerate inhalation of a short acting Beta-2 agonist.

• Changes in antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days before Screening or between Screening and the next visit.

• Changes in physiotherapy technique or schedule within 7 days before 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 or serum chemistry at Screening (aspartate aminotransferase [AST], alanine aminotransferase [ALT] greater than 5 times the upper limit of normal range; Creatinine greater than 2 times the upper limit of normal range).

• Positive pregnancy test at Screening.

• Female of childbearing potential who was lactating or in the opinion of the investigator was not practicing acceptable birth control.

• 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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• AZLI 75 mg two times a day (BID)/three times a day (TID)

• Placebo two times a day (BID)/three times a day (TID)

Locations

Country	Name	City	State
United States	Akron Children's Hospital	Akron	Ohio
United States	Albany Medical College	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory Healthcare	Atlanta	Georgia
United States	Medical College of Georgia	Augusta	Georgia
United States	Children's Hospital, Boston	Boston	Massachusetts
United States	Floating Hospital for Children	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Long Island College Hospital	Brooklyn	New York
United States	Children's Hospital of Buffalo	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Children's Memorial Hospital/Northwestern University	Chicago	Illinois
United States	Pediatric Pulmonary Associates, South Carolina	Columbia	South Carolina
United States	Columbus Children's Hospital, Ohio State University	Columbus	Ohio
United States	Children's Medical Center	Dayton	Ohio
United States	Children's Hospital	Denver	Colorado
United States	Children's Hospital of Michigan/Wayne State University	Detroit	Michigan
United States	University of Florida Health Sciences Center	Gainesville	Florida
United States	Chicago Children's Asthma Respiratory and Exercise Specialists	Glenview	Illinois
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State University Hershey Medical Center	Hershey	Pennsylvania
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Nemours Children's Clinic, Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California, San Diego	La Jolla	California
United States	Children's Lung Specialists, Ltd.	Las Vegas	Nevada
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Loyola University Medical Center	Maywood	Illinois
United States	University of Miami School of Medicine	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	West Virginia University	Morgantown	West Virginia
United States	Morristown Memorial Hospital	Morristown	New Jersey
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Columbia University Medical Center	New York	New York
United States	North Suburban Pulmonary / Critical Care Consultants	Niles	Illinois
United States	Kaiser Permanente Medical Care Program	Oakland	California
United States	Dr. Santiago Reyes	Oklahoma City	Oklahoma
United States	Children's Hospital, Orange Co.	Orange	California
United States	Nemours Children's Clinic	Orlando	Florida
United States	Stanford University Hospital and Medical Center	Palo Alto	California
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburg	Pittsburg	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Pediatric Pulmonary Center	Richmond	Virginia
United States	UC Davis Medical Center	Sacramento	California
United States	Alamo Clinical Research Associates	San Antonio	Texas
United States	Children's Hospital and Regional Medical Center	Seattle	Washington
United States	Pediatric Pulmonary Associates, Florida	St. Petersburg	Florida
United States	State University of New York Stony Brook	Stony Brook	New York
United States	Children's Hospital of Westchester Medical Center/New York Medical College	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Need for Inhaled or Intravenous (IV) Antipseudomonal Antibiotics	The primary endpoint was time to need for a course of inhaled or IV antipseudomonal antibiotics with documented physician assessment of need for antibiotics. Antipseudomonal Antibiotic need was documented based on the presence of at least one of the following four symptoms predictive of pulmonary exacerbation: decreased exercise tolerance, increased cough, increased sputum / chest congestion, decreased appetite, or other.	Day 0 to Day 84 (end of study)	No
Secondary	Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score	The CFQ-R was administered at Day -28, baseline, Day 14, Day 28, and Day 84 (end of study). The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores [units]: 0-100; higher scores indicate fewer symptoms).	Day 0 to Day 28	No
Secondary	Percent Change in Forced Expiratory Volume in 1 Second (FEV1) (L)	Spirometry was performed at each visit. FEV1 was recorded according to American Thoracic Society (ATS) guidelines.; FEV1(L) is the measurement of the volume of air (expressed in liters) exhaled in 1 second.; The percent change in this parameter from Day 0 to Day 28 was determined for each treatment group.	Day 0 to Day 28	No
Secondary	Number of Hospitalization Days	Details of all hospitalizations, including the dates of admission and discharge, were recorded on the electronic case report form (eCRF).	Day 0 to Day 84	No
Secondary	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	No