Safety of AZLI in Children With Cystic Fibrosis (CF) and Chronic Pseudomonas Aeruginosa in the Lower Airways (PALS)

Open-Label Phase 3 Trial to Evaluate the Safety of Aztreonam 75 mg Powder and Solvent for Nebuliser Solution/Aztreonam for Inhalation Solution (AZLI) in Children With Cystic Fibrosis (CF) and Chronic Pseudomonas Aeruginosa (PA) in the Lower Airways

This was an open-label, multicenter study in children ≤ 12 years of age with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (PA) infection in the lower airways using three 28-day courses of Aztreonam for Inhalation Solution (AZLI) 75 mg three times daily, each followed by 28 days off AZLI. The total treatment duration was to be 6 months.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Pseudomonas Aeruginosa
• Intervention / Treatment: Drug: AZLI

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • C.H.U de Bordeaux
  • Lisieux, France
    • Centre Hospitalier Robert Bissons
  • Paris Cedex 15, France
    • Hôpital Necker Enfants Malades
• Germany
  • Berlin, Germany
    • Charite Campus Virchow Klinikum
  • Bochum, Germany
    • Universitatsklinik St. Josef-Hospital
  • Erlandgen, Germany
    • Kinder und Jugendklinik, Abteilung Lungen Bronchialheikunde
  • Essen, Germany
    • Universitätsklinikum Essen
  • Frankfurt, Germany
    • J.W. Goethe University Hopsital
• Italy
  • Catania, Italy
    • Azienda Ospedaliero Universitaria - Policlinico di Catania
  • Florence, Italy
    • A. Meyer Children Hospital Florence
  • Verona, Italy
    • Azienda Ospedaliera Instituti Ospitalieri di Verona
• Poland
  • Gdansk, Poland
    • Specjalistyczny Zespot Opieki Zdrowotnej nad Matka i Dzieckiem
  • Rabka Zdroj, Poland
    • Instytut Gruzlicy i Chorob Pluc
  • Warszawa, Poland
    • Instytut Matki i Dziecka
• Spain
  • Barcelona, Spain
    • Pediatric Pneunmonology and Cystic Fibrosis Clinic
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • Hospital Infantil Universitario Niño Jesús
  • Madrid, Spain
    • Hospital Infantil La Paz
  • Malaga, Spain
    • Hosp. Mat-Inf. Carlos Haya
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital - Denver
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic - Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital & Clinics
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria:

  • Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test OR
  • Abnormal nasal transepithelial potential difference (NPD) test OR
  • A genotype with 2 identifiable mutations consistent with CF AND
  • One or more clinical features consistent with CF.
• Documented positive lower respiratory tract culture for PA at the screening visit plus two documented positive lower respiratory tract cultures for PA within 12 months prior to study entry (must have been a minimum 3 months apart.)
• Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no chest radiograph findings at screening that would have required administration of IV antipseudomonal antibiotics, oxygen supplementation, or hospitalization.

Exclusion Criteria:

• Use of IV or inhaled antipseudomonal antibiotics within 14 days of study entry
• Presence of a condition or abnormality that would have compromised the participant's safety or the quality of study data, in the opinion of the investigator
• History of sputum or throat swab culture yielding Burkholderia spp. within 2 years prior to screening visit
• History of hypersensitivity/adverse reaction to aztreonam
• History of hypersensitivity/adverse reaction to beta-agonists
• History of lung transplantation
• Administration of any investigational drug or device within 30 days prior to screening visit or within 6 half-lives of the investigational drug (whichever was longer)
• Hospitalization for pulmonary-related illness within 28 days prior to screening visit
• Changes in or initiation of chronic azithromycin treatment within 28 days prior to screening visit
• Changes in or initiation of hypertonic saline treatment within 7 days prior to screening visit; for subjects on a stable regimen of hypertonic saline (28 days on/28 days off), beginning or ending a cycle of hypertonic saline was allowed
• Changes in antimicrobial, bronchodilator (BD), corticosteroid or dornase alfa medications within 7 days prior to screening visit;
• Changes in physiotherapy technique or schedule within 7 days prior to screening visit
• Abnormal renal or hepatic function results at most recent test within the previous 90 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Open-label AZLI; Participants received three 28-day courses of AZLI, each followed by 28 days off-treatment.	Drug: AZLI; AZLI 75 mg was administered 3 times daily via the investigational nebulizer.; Other Names: Cayston®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons	Participants who discontinued study drug due to safety or tolerability reasons were defined as those with "Adverse Event (AE)/Safety or Tolerability" on the Study Drug Completion electronic case report form as the reason for early discontinuation. The 95% confidence interval (CI) was calculated using the exact binomial method.	Baseline to Day 168

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years	The change in FEV1 % predicted was assessed at the end of each 28-day AZLI treatment course. FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex, race, and body composition.	Baseline to Day 28, 84, and 140
Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years	The change in CFQ-R RSS score was assessed at the end of each 28-day AZLI treatment course. The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms.	Baseline to Day 28, 84, and 140
Change in Pseudomonas Aeruginosa (PA) Sputum Density	The change in PA sputum density (log10 colony-forming units per gram [cfu/g]) was assessed at the end of each 28-day AZLI treatment course.	Baseline to Day 28, 84, and 140
Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics	The percentage of participants who used additional (non-study) antipseudomonal antibiotics (IV, inhaled, oral, IV/inhaled, IV/inhaled/oral) was summarized (number and percent) for all subjects.	Baseline to Day 168
Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event		Baseline to Day 168
Number of Days Participants Were Hospitalized Due to a Respiratory Event	The average number of days hospitalized due to a respiratory event, among the 11 participants who were hospitalized for respiratory event, was reported.	Baseline to Day 168
Percentage of Participants With Pulmonary Exacerbations	Pulmonary exacerbations were defined as respiratory hospitalizations or discrete courses of non-study IV/inhaled antipseudomonal antibiotics. Use of oral antibiotics alone for respiratory signs or symptoms was considered to be representative of milder clinical events and, therefore, was not included in the definition of pulmonary exacerbations.	Baseline to Day 168
Time to Pulmonary Exacerbation	The median days to first pulmonary exacerbation was summarized using Kaplan-Meier (KM) summary statistics.	Baseline to Day 168
Percentage of Participants With Study-drug Induced Bronchospasm	Study-drug induced bronchospasm (airway reactivity) was assessed at the baseline visit as the percent change in FEV1 from the pretreatment measurement to 30 minutes following treatment for subjects ≥ 6 years or as from the Investigator's assessment for subjects < 6 years.	Pretreatment at Baseline to 30 minutes following treatment
Adverse Event Rates Adjusted for Study Duration	Adverse events occurring in ≥ 5% of participants adjusted for study duration were summarized. The adjustment was made by using a standardized rate calculated as the sum of study duration across patients divided by 28 for the total number of patient months. Rate calculations presented are the number of adverse events (AEs) per patient month.	Baseline to Day 168

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ACTUAL): April 1, 2013
• Study Completion (ACTUAL): April 1, 2013

Study Registration Dates

• First Submitted: July 26, 2011
• First Submitted That Met QC Criteria: July 27, 2011
• First Posted (ESTIMATE): July 28, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): May 29, 2014
• Last Update Submitted That Met QC Criteria: May 12, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Pseudomonas aeruginosa; CF; PA; AZLI; aztreonam; Chronic Pseudomonas aeruginosa
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Pseudomonas Infections
• Other Study ID Numbers: GS-US-205-0160