title: Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis.
abstract: Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis.
  
  
  BACKGROUND
  NCT00769119.
authors: Lung Investigations Unit, Medicine - University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK. Rob.Stockley@uhb.nhs.uk
authors: Robert
authors: R
authors: Stockley
authors: Anthony
authors: A
authors: De Soyza
authors: Kulasiri
authors: K
authors: Gunawardena
authors: John
authors: J
authors: Perrett
authors: Kristina
authors: K
authors: Forsman-Semb
authors: Neil
authors: N
authors: Entwistle
authors: Noel
authors: N
authors: Snell
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001987:Bronchiectasis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D053491:Proteinase Inhibitory Proteins, Secretory / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015656:Respiratory Mechanics / Q000187:drug effects; D013183:Sputum / Q000166:cytology / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D016138:Walking / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D053491:Proteinase Inhibitory Proteins, Secretory; D011728:Pyridones; D013450:Sulfones; 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