A Randomised, Placebo-Controlled, Dose-Finding Study Of AZD9668, An Oral Inhibitor of Neutrophil Elastase, in Patients with Chronic Obstructive Pulmonary Disease Treated with Tiotropium
- 12 March 2012
- journal article
- research article
- Published by Informa UK Limited in COPD: Journal of Chronic Obstructive Pulmonary Disease
- Vol. 9 (2), 111-120
- https://doi.org/10.3109/15412555.2011.641803
Abstract
AZD9668 is a fully reversible, selective, oral inhibitor of neutrophil elastase, a protease implicated in chronic obstructive pulmonary disease (COPD). Efficacy, safety and tolerability of AZD9668 (5, 20 and 60 mg bid) were compared with placebo in a randomised, double-blind, placebo-controlled, 12-week, Phase IIb trial (NCT00949975: approved by an Investigational Review Board), in patients with symptomatic COPD receiving maintenance tiotropium. The primary endpoint was pre-bronchodilator forced expiratory volume in 1 second (FEV₁). Secondary endpoints included forced vital capacity and inspiratory capacity, peak expiratory flow, Breathlessness, Cough and Sputum Scale score, exercise capacity, quality of life (QoL), exacerbation assessments, safety and pharmacokinetics. Exploratory endpoints included inflammatory and tissue degradation biomarkers. A total of 838 patients were randomised to AZD9668 5 mg bid (212 patients), 20 mg bid (206 patients), 60 mg bid (202 patients) or placebo (218 patients). AZD9668 showed no effect on lung function, respiratory signs and symptoms, QoL or biomarkers. At end of treatment, the change in mean pre-bronchodilator FEV₁ for AZD9668 60 mg bid compared with placebo was 0.00L (95% confidence interval: -0.05, 0.04; p = 0.873). Overall, AZD9668 was well tolerated; the numbers of patients with adverse events (AEs), serious AEs and AEs leading to discontinuation were similar in each of the four study groups. AZD9668 60 mg bid showed no clinical benefit and no effect on biomarkers of inflammation or tissue degradation when added to tiotropium in patients with COPD. These results raise important questions for future investigation of anti-inflammatory and disease-modifying agents in patients with COPD.Keywords
This publication has 16 references indexed in Scilit:
- The fibrinogen cleavage product A -Val360, a specific marker of neutrophil elastase activity in vivoThorax, 2011
- Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH studyThe Clinical Respiratory Journal, 2010
- Defining Disease Modification in Chronic Obstructive Pulmonary DiseaseCOPD: Journal of Chronic Obstructive Pulmonary Disease, 2009
- A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary DiseaseNew England Journal of Medicine, 2008
- Advances in Neutrophil Biology: Clinical ImplicationsChest, 2008
- Effect of Pharmacotherapy on Rate of Decline of Lung Function in Chronic Obstructive Pulmonary DiseaseAmerican Journal of Respiratory and Critical Care Medicine, 2008
- The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary DiseaseNew England Journal of Medicine, 2004
- MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trialEuropean Respiratory Journal, 1996
- Comparison of Properties of Membrane Bound Versus Soluble Forms of Human Leukocytic Elastase and Cathepsin GBiological Chemistry Hoppe-Seyler, 1994
- ONO-5046, a novel inhibitor of human neutrophil elastaseBiochemical and Biophysical Research Communications, 1991