PMID- 22458939
OWN - NLM
STAT- MEDLINE
DCOM- 20130329
LR  - 20220408
IS  - 1541-2563 (Electronic)
IS  - 1541-2563 (Linking)
VI  - 9
IP  - 2
DP  - 2012 Apr
TI  - 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.
PG  - 111-20
LID - 10.3109/15412555.2011.641803 [doi]
AB  - 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 (FEV(1)). 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 FEV(1) 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.
FAU - Vogelmeier, Claus
AU  - Vogelmeier C
AD  - Universitatsklinikum Giessen und Marburg, Marburg, Germany. 
      Claus.Vogelmeier@med.uni-marburg.de
FAU - Aquino, Teresita O
AU  - Aquino TO
FAU - O'Brien, Christopher D
AU  - O'Brien CD
FAU - Perrett, John
AU  - Perrett J
FAU - Gunawardena, Kulasiri A
AU  - Gunawardena KA
LA  - eng
SI  - ClinicalTrials.gov/NCT00949975
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - COPD
JT  - COPD
JID - 101211769
RN  - 0 (Biomarkers)
RN  - 0 (Bronchodilator Agents)
RN  - 0 (Pyridones)
RN  - 0 (Scopolamine Derivatives)
RN  - 0 (Sulfones)
RN  - 6Y5629322X 
      (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)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
RN  - XX112XZP0J (Tiotropium Bromide)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers/analysis
MH  - Bronchodilator Agents/administration & dosage/adverse effects/*therapeutic use
MH  - Double-Blind Method
MH  - Drug Therapy, Combination
MH  - Female
MH  - Forced Expiratory Volume/*drug effects
MH  - Humans
MH  - Leukocyte Elastase/*antagonists & inhibitors
MH  - Male
MH  - Middle Aged
MH  - Pulmonary Disease, Chronic Obstructive/*drug therapy
MH  - Pyridones/*administration & dosage/adverse effects
MH  - Quality of Life
MH  - Scopolamine Derivatives/*therapeutic use
MH  - Spirometry
MH  - Sulfones/*administration & dosage/adverse effects
MH  - Tiotropium Bromide
MH  - Treatment Outcome
EDAT- 2012/03/31 06:00
MHDA- 2013/03/30 06:00
CRDT- 2012/03/31 06:00
PHST- 2012/03/31 06:00 [entrez]
PHST- 2012/03/31 06:00 [pubmed]
PHST- 2013/03/30 06:00 [medline]
AID - 10.3109/15412555.2011.641803 [doi]
PST - ppublish
SO  - COPD. 2012 Apr;9(2):111-20. doi: 10.3109/15412555.2011.641803.