Phase 3 Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy Regimen for the Treatment of Chronic Pseudomonas Aeruginosa Infection in Patients With CF (AZLI CAT)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy (CAT) Regimen of Inhaled Antibiotics for the Treatment of Chronic Pulmonary Pseudomonas Aeruginosa Infection in Subjects With Cystic Fibrosis

The primary objective of this study is to evaluate the safety and efficacy of a CAT regimen with aztreonam for inhalation solution (AZLI) and tobramycin inhalation solution (TIS) in adult and pediatric subjects with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection. Participants will be enrolled in a 28 day TIS run-in phase, and will be eligible for randomization in the comparative phase if they have not received non-study oral antibiotics for a respiratory event, or IV or inhaled antibiotics for any indication between Visits 2 and 3, have not developed a condition requiring hospitalization or other change in clinical status which, in the opinion of the investigator would preclude their ability to continue in the study, and have demonstrated at least 50% TIS compliance. Participants enrolled in the comparative phase will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI or placebo for 28 days followed by TIS for 28 days.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: AZLI; Drug: Tobramycin inhalation solution; Drug: Placebo to match AZLI

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • La Jolla, California, United States, 92093
      • University of California - San Diego
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Oakland, California, United States, 94611
      • Kaiser Permanente Medical Center
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington DC, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Altamonte Springs, Florida, United States, 32701
      • Central Florida Pulmonary Group
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Hollywood, Florida, United States, 33021
      • South Broward Hospital dba Memorial Healthcare System
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic - Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children
    • Orlando, Florida, United States, 32801
      • Nemours Children's Clinic - Orlando
    • Pensacola, Florida, United States, 32504
      • Nemour's Children's Clinic
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30084
      • Emory Cystic Fibrosis Center
    • Augusta, Georgia, United States, 30912
      • Georgia Health
  • Idaho
    • Boise, Idaho, United States, 37012
      • St. Lukes Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Glenview, Illinois, United States, 60025
      • Chicago CF Care Specialists NFP dba Cystic Fibrosis Institure
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maine
    • Portland, Maine, United States, 38103
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48201
      • Harper University Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health - Helen DeVos Children's Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • St. Louis, Missouri, United States, 63104
      • St. Louis University - Cardinal Glennon Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89107
      • Children's Lung Specialists
  • New Hampshire
    • Bedford, New Hampshire, United States, 03110
      • Dartmouth Hitchcock Specialty Care Clinic
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Morristown Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • UNM Clinical and Translational Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New Hyde Park, New York, United States, 11042
      • Long Island Jewish Medical Center - Adult CF & Bronchiectasis Center
    • New York, New York, United States, 10032
      • Gunnar Esiason Adult CF and Lung Program
    • Syracuse, New York, United States, 13210
      • SUNY Upstate University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cincinnati, Ohio, United States, 45267
      • UC Health - University of Cincinnati
    • Toledo, Ohio, United States, 43606
      • The Toledo Hospital/Toledo Children's Hospital CF Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • OU Health Sciences Center
    • Oklahoma City, Oklahoma, United States, 73112
      • Santiago Reyes, MD
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Clinic
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Drexel University College of Medicine
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Children's Hospital
    • Memphis, Tennessee, United States, 28103
      • Children's Foundation Research Institute/UTHSC
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Children's Hospital
  • Texas
    • Austin, Texas, United States, 78723
      • Austin Children's Chest Associates
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Ft. Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • San Antonio, Texas, United States, 78212
      • Alamo Clinical Research Associates
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Vermont
    • Colchester, Vermont, United States, 05446
      • Vermont Lung Center at The University of Vermont
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Norfolk, Virginia, United States, 23510
      • Children's Hospital of The King's Daughters
    • Richmond, Virginia, United States, 23298
      • VCU Children's Hospital
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201
      • Children's Hospital of Wisconsin

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:

• Confirmed diagnosis of CF
• Presence of PA in 2 lower respiratory tract cultures in the 12 months prior to screening
• Forced expiratory volume (FEV)1 ≥ 25 and ≤ 75% predicted
• History of 1 hospitalization or 1 course of IV antibiotics for an acute respiratory exacerbation in the 12 months prior to screening

Exclusion Criteria:

• Concurrent use of oral, IV or inhaled antibiotics at enrollment
• Concurrent hospitalization at enrollment
• History of local or systemic hypersensitivity to monobactams or aminoglycoside antibiotics or history of aminoglycoside antibiotic associated toxicity

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AZLI; Participants will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI for 28 days followed by TIS for 28 days.	Drug: AZLI; Aztreonam for Inhalation Solution (AZLI) 75 mg 3 times daily combined with diluent administered using an eFlow nebulizer; Other Names: Cayston®; Drug: Tobramycin inhalation solution; Tobramycin inhalation solution (TIS) 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor; Other Names: TOBI®
Placebo Comparator: Placebo; Participants will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS for 28 days.	Drug: Tobramycin inhalation solution; Tobramycin inhalation solution (TIS) 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor; Other Names: TOBI®; Drug: Placebo to match AZLI; Placebo to match AZLI 3 times daily combined with diluent administered using an eFlow nebulizer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24	PDEs were characterized by a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of non-study IV or inhaled antibiotics and be verified by a blinded independent adjudication committee.	Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20)	FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex and body composition. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.	Comparative Phase: Baseline and Weeks 4, 12 and 20
Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs		Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Time to First Protocol-defined Pulmonary Exacerbation	The time to first protocol-defined pulmonary exacerbation was calculated using the Kaplan-Meier method.	Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Rate of Hospitalizations for a Respiratory Event	The rate of hospitalizations for a respiratory event per participant year was calculated using negative binomial regression analysis.	Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20)	Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.	Comparative Phase: Baseline and Weeks 4, 12 and 20

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Mark Bresnik, MD, Gilead Sciences

Publications and helpful links

General Publications

• Flume PA, Clancy JP, Retsch-Bogart GZ, Tullis DE, Bresnik M, Derchak PA, Lewis SA, Ramsey BW. Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis. J Cyst Fibros. 2016 Nov;15(6):809-815. doi: 10.1016/j.jcf.2016.05.001. Epub 2016 May 24.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: July 13, 2012
• First Submitted That Met QC Criteria: July 16, 2012
• First Posted (Estimate): July 17, 2012

Study Record Updates

• Last Update Posted (Estimate): May 9, 2016
• Last Update Submitted That Met QC Criteria: April 6, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• 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; Anti-Infective Agents; Anti-Bacterial Agents; Tobramycin
• Other Study ID Numbers: GS-US-205-0170; 2015-000398-11 (EudraCT Number)