title: Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.
abstract: BACKGROUND
  The clinical benefit of inhaled antibiotics in non-cystic fibrosis bronchiectasis has not been established in randomised controlled trials. We aimed to assess safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with non-cystic fibrosis bronchiectasis and Gram-negative bacterial colonisation.
  
  
  METHODS
  AIR-BX1 and AIR-BX2 were two double-blind, multicentre, randomised, placebo-controlled phase 3 trials, which included patients aged 18 years or older who had bronchiectasis and history of positive sputum or bronchoscopic culture for target Gram-negative organisms. Patients were randomly assigned to receive either AZLI or placebo (1:1). Randomisation was done without stratification and the code was generated by a Gilead designee. In both studies, two 4-week courses of AZLI 75 mg or placebo (three-times daily; eFlow nebulizer) were each followed by a 4-week off-treatment period. Primary endpoint was change from baseline Quality of Life-Bronchiectasis Respiratory Symptoms scores (QOL-B-RSS) at 4 weeks. These trials are registered with ClinicalTrials.gov, numbers are NCT01313624 for AIR-BX1 and NCT01314716 for AIR-BX2.
  
  
  RESULTS
  We recruited participants from 47 ambulatory clinics for AIR-BX1 and 65 ambulatory clinics for AIR-BX2; studies were done between April 25, 2011, and July 1, 2013. In AIR-BX1, of the 348 patients screened, 134 were randomly assigned to receive AZLI and 132 to receive placebo. In AIR-BX2, of the 404 patients screened, 136 were randomly assigned to receive AZLI and 138 to receive placebo. The difference between AZLI and placebo for adjusted mean change from baseline QOL-B-RSS was not significant at 4 weeks (0.8 [95% CI -3.1 to 4.7], p=0.68) in AIR-BX1, but was significant (4.6 [1.1 to 8.2], p=0.011) in AIR-BX2. The 4.6 point difference in QOL-B-RSS after 4 weeks in AIR-BX2 was not deemed clinically significant. In both studies, treatment-related adverse events were more common in the AZLI group than in the placebo group, as were discontinuations from adverse events. The most commonly reported treatment-emergent adverse events were dyspnea, cough, and increased sputum. Each was more common for AZLI-treated than for placebo-treated patients, but the incidences were more balanced in AIR-BX2.
  
  
  CONCLUSIONS
  AZLI treatment did not provide significant clinical benefit in non-cystic fibrosis bronchiectasis, as measured by QOL-B-RSS, suggesting a continued need for placebo-controlled studies to establish the clinical benefit of inhaled antibiotics in patients with this disorder.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care, Oregon Health and Science University, Portland, OR, USA. Electronic address: barkera@ohsu.edu.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Barker
authors.affiliation: Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Georgetown University, Washington DC, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: O'Donnell
authors.affiliation: Departments of Medicine and Pediatrics, Medical University of South Carolina, Charleston SC, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Flume
authors.affiliation: Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.affiliation: Scottsdale Healthcare Shea Medical Center, Scottsdale, AZ, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ruzi
authors.affiliation: Department of Pneumology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: de Gracia
authors.affiliation: Department of Pulmonary Diseases, Medical Centre Alkmaar, Alkmaar, Netherlands.
authors.forename: Wim G
authors.initials: WG
authors.lastname: Boersma
authors.affiliation: Freeman Hospital Bronchiectasis Service and Transplantation and Immunobiology Group, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: De Soyza
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Shao
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Haas
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Lewis
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Leitzinger
authors.affiliation: Cardeas Pharma Corp., Seattle, WA, USA.
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Montgomery
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: McKevitt
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gossage
authors.affiliation: Department of Psychology and Pediatrics, University of Miami, and Behavioral Health Sciences Research, Coral Gables, FL, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Quittner
authors.affiliation: Gilead Sciences Inc., Seattle, WA, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: O'Riordan
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001398:Aztreonam / Q000008:administration & dosage* / Q000009:adverse effects; D001987:Bronchiectasis / Q000188:drug therapy* / Q000209:etiology; D003371:Cough / Q000139:chemically induced; D004311:Double-Blind Method; D004417:Dyspnea / Q000139:chemically induced; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D013183:Sputum / Q000187:drug effects / Q000382:microbiology; D013995:Time; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D001398:Aztreonam