Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Cystic Fibrosis Patients With P. Aeruginosa (AIR-CF2)

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)

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).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo two times a day (BID)/three times a day (TID); Drug: AZLI 75 mg two times a day (BID)/three times a day (TID)

Detailed 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).

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (pooled two times a day [BID]/three times a day [TID])	Drug: Placebo two times a day (BID)/three times a day (TID)
Experimental: AZLI (pooled two times a day [BID]/three times a day [TID])	Drug: AZLI 75 mg two times a day (BID)/three times a day (TID)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Other Pathogens	Sputum samples were collected at all visits for quantitative and qualitative culture for Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. Number of participants with other pathogens at baseline and at the end of treatment (28 days) are reported.	Day 0 and Day 28
Minimum Concentration of Aztreonam Inhibiting 50% (MIC50) and 90% (MIC90) of All PA Isolates (μg/mL)	The aztreonam susceptibility of PA isolates from sputum samples (collected at all visits) was assessed. MIC50 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 50% of isolates from a particular organism). MIC90 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 90% of isolates from a particular organism). MIC50 and MIC90 values are single measurements for the entire population and not measured on a per-participant basis.	Day 0 to Day 28

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Principal Investigator: Karen McCoy, MD, Nationwide Children's Hospital

Publications and helpful links

General Publications

• Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009 Jun;135(6):1610-1618. doi: 10.1378/chest.08-1190. Epub 2009 May 15.
• McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008 Nov 1;178(9):921-8. doi: 10.1164/rccm.200712-1804OC. Epub 2008 Jul 24.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: March 1, 2005
• First Submitted That Met QC Criteria: March 1, 2005
• First Posted (Estimate): March 2, 2005

Study Record Updates

• Last Update Posted (Estimate): March 11, 2011
• Last Update Submitted That Met QC Criteria: February 16, 2011
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: CP-AI-005