Clinical trial NCT00712166: Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis, Mild Lung Disease, and P. Aeruginosa
Official title: A Double-Blind, Multicenter, Multinational, Randomized, Placebo-Controlled Trial Evaluating Aztreonam Lysine For Inhalation in Patients With Cystic Fibrosis, Mild Lung Disease, and P. Aeruginosa (AIR-CF4)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Lung Infection
Pseudomonas Aeruginosa
Keywords: cystic fibrosis
pseudomonas aeruginosa
lung infection
CFQ-R
inhaled antibiotic
aztreonam lysine
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-07-09
Enrollment: 160
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
timeFrame: Day 0 to Day 28
Secondary outcomes:
measure: Change From Baseline in CFQ-R RSS Score at Day 14
timeFrame: Day 0 to Day 14
measure: Change From Baseline in CFQ-R RSS Score at Day 42
timeFrame: Day 0 to Day 42
measure: Change From Baseline in CFQ-R Physical Functioning Domain Score
timeFrame: Day 0 to Day 28
measure: Number of Participants Using Additional (Nonprotocol-specified) Antipseudomonal Antibiotics During Study
timeFrame: Day 0 to Day 42
measure: Number of Participants Hospitalized During Study
timeFrame: Day 0 to Day 42
measure: Change From Baseline in Log10 Pseudomonas Aeruginosa (PA) Colony Forming Units (CFUs) in Sputum at Day 28
timeFrame: Day 0 to Day 28
measure: Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
timeFrame: Day 0 to Day 28
Other outcomes:
measure: Number of Participants Testing Positive for Other Respiratory Pathogens
timeFrame: Day 0 to Day 28
measure: The Minimum Concentrations of Aztreonam That Inhibit 50% and 90% of All PA Isolates (MIC50 and MIC90, Respectively)
timeFrame: Day 0 to Day 28
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Tucson
country: United States
facility: University Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences, Division of Pulmonary and Critical Care Medicine
state: Arkansas
city: Oakland
country: United States
facility: Kaiser Permanente
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Aurora
country: United States
facility: The Children's Hospital
state: Colorado
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University, Outpatient Clinical Research Facility
state: Indiana
city: Indianapolis
country: United States
facility: James Whitcomb Riley Hospital for Children
state: Indiana
city: Boston
country: United States
facility: Children's Hospital, Boston
state: Massachusetts
city: Boston
country: United States
facility: Tufts Medical Center, Pediatric Pulmonary Clinic
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: The Children's Hospital of Michigan, Detroit Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: The Minnesota CF Center, University of Minnesota Medical Center
state: Minnesota
city: Las Vegas
country: United States
facility: Children's Lung Specialists
state: Nevada
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Buffalo
country: United States
facility: The Lung & Cystic Fibrosis Center, University of Buffalo Pediatric Associates, Inc., Women & Children's Hospital of Buffalo
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Toledo
country: United States
facility: Toledo Children's Hospital/Toledo Hospital, Cystic Fibrosis Research Center
state: Ohio
city: Oklahoma City
country: United States
facility: Santiago Reyes, MD
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine, Pulmonary Associates
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: St. Christopher's Hospital for Children
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center
state: Washington
city: Westmead
country: Australia
facility: Department of Respiratory Medicine, The Children's Hospital at Westmead
state: New South Wales
city: Westmead
country: Australia
facility: Department of Respiratory Medicine, Westmead Hospital
state: New South Wales
city: Chermside
country: Australia
facility: The Prince Charles Hospital, Adult Cystic Fibrosis Centre
state: Queensland
city: Herston
country: Australia
facility: Respiratory Medicine, Royal Children's Hospital
state: Queensland
city: Perth
country: Australia
facility: Child and Adolescent Health Services, Princess Margaret Hospital
state: Western Australia
city: Montreal
country: Canada
facility: Centre de Recherche du CHUM
state: Quebec
Study officials:
affiliation: Royal Children's Hospital, Brisbane, QLD, Australia
name: Claire Wainwright, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital & Regional Medical Center, Seattle WA, USA
name: Ron Gibson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wainwright CE, Quittner AL, Geller DE, Nakamura C, Wooldridge JL, Gibson RL, Lewis S, Montgomery AB. Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa. J Cyst Fibros. 2011 Jul;10(4):234-42. doi: 10.1016/j.jcf.2011.02.007. Epub 2011 Mar 26.