title: AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD.
abstract: BACKGROUND
  Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60 mg bid during Phase I/IIa development.
  
  
  METHODS
  This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60 mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George's respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments.
  
  
  RESULTS
  Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo.
  
  
  CONCLUSIONS
  Three months' treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents.
authors.affiliation: Division of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland. piotr.kuna@umed.lodz.pl
authors.forename: Piotr
authors.initials: P
authors.lastname: Kuna
authors.forename: Martin
authors.initials: M
authors.lastname: Jenkins
authors.forename: Christopher D
authors.initials: CD
authors.lastname: O'Brien
authors.forename: William A
authors.initials: WA
authors.lastname: Fahy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019819:Budesonide / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D015656:Respiratory Mechanics / Q000187:drug effects; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001993:Bronchodilator Agents; D004338:Drug Combinations; D004983:Ethanolamines; D005938:Glucocorticoids; D011728:Pyridones; D013450:Sulfones; D019819:Budesonide; C568080:N-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide; D019272:Leukocyte Elastase; D000068759:Formoterol Fumarate