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

COPD: Journal of Chronic Obstructive Pulmonary Disease

Volumn 9, Issue 2, 2012, Pages 111-120

  Vogelmeier, Claus ^a   Aquino, Teresita O ^b   O'Brien, Christopher D ^c   Perrett, John ^c   Gunawardena, Kulasiri A ^c  

^a UNIVERSITY HOSPITAL MARBURG   (Germany)

^b Veterans Memorial Medical Center   (Philippines)

^c ASTRAZENECA   (United Kingdom)

Author keywords

Efficacy, inflammatory lung disease; Pharmacokinetics; Safety, tolerability

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; AZD 9668; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; C REACTIVE PROTEIN; CREATININE; HANDIHALER; INTERLEUKIN 6; INTERLEUKIN 8; LEUKOCYTE ELASTASE; PLACEBO; SALBUTAMOL SULFATE; TIOTROPIUM BROMIDE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BIODEGRADATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CONTROLLED STUDY; COUGHING; DISEASE EXACERBATION; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; DYSPNEA; EXERCISE; FEMALE; FORCED EXPIRATORY VOLUME; FORCED VITAL CAPACITY; HAZARD RATIO; HUMAN; INFLAMMATION; INSPIRATORY CAPACITY; LUNG EMBOLISM; MAJOR CLINICAL STUDY; MALE; MEDICAL HISTORY; MULTICENTER STUDY; OUTCOME ASSESSMENT; PEAK EXPIRATORY FLOW; PHASE 2 CLINICAL TRIAL; PNEUMONIA; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; RATING SCALE; RHINOPHARYNGITIS; SCORING SYSTEM; SIDE EFFECT; SMOKING; TREATMENT DURATION; UPPER RESPIRATORY TRACT INFECTION; XEROSTOMIA;

ADMINISTRATION, ORAL; ADULT; AGED; AGED, 80 AND OVER; BIOLOGICAL MARKERS; BRONCHODILATOR AGENTS; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; FEMALE; FORCED EXPIRATORY VOLUME; HUMANS; LEUKOCYTE ELASTASE; MALE; MIDDLE AGED; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; PYRIDONES; QUALITY OF LIFE; SCOPOLAMINE DERIVATIVES; SPIROMETRY; SULFONES; TREATMENT OUTCOME;

EID: 84859373133     PISSN: 15412555     EISSN: 15412563     Source Type: Journal    
DOI: 10.3109/15412555.2011.641803     Document Type: Article

References (23)

1. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available from: http://www.goldcopd.org/(accessed 22 December, 2011).
2. Quint JK, Wedzicha JA. The neutrophil in chronic obstructive pulmonary disease. J Allergy Clin Immunol 2007; 119:1065-1071. (Pubitemid 46654162)
3. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:2645-2653. (Pubitemid 38787999)
4. Cowburn AS, Condliff e AM, Farahi N, Summers C, Chilvers ER. AdVances in neutrophil biology: clinical implications. Chest 2008; 134:606-612.
5. Kawabata K, Suzuki M, Sugitani M, Imaki K, Toda M, Miyamoto T. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun 1991; 177:814-820.
6. Lucas SD, Costa E, Guedes RC, Moreira R. Targeting COPD: AdVances on low-molecular-weight inhibitors of human neutrophil elastase. Med Res Rev 2011; [Epub ahead of print].
7. Stevens T, Ekholm K, Granse M, Lindahl M, Kozma V, Jungar C, Ottosson T, Falk-Hakansson H, Churg A, Wright JL, Lal H, Sanfridson A. AZD9668: pharmacological characterisation of a novel oral inhibitor of neutrophil elastase. J Pharmacol Exp Ther 2011; 339:313-320.
8. Gunawardena K, Gullstrand H, Perrett J. Safety, tolerability and pharmacokinetics of AZD9668, an oral neutrophil elastase inhibitor, in healthy subjects and patients with COPD. Eur Respir J 2010; 203s.
9. Luisetti M, Sturani C, Sella D, Madonini E, Galavotti V, Bruno G, Peona V, Kucich U, Dagnino G, Rosenbloom J, Starcher B, Grassi C. MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial. Eur Respir J 1996; 9:1482-1486. (Pubitemid 26233794)
10. Bangalore N, Travis J. Comparison of properties of membrane bound versus soluble forms of human leukocytic elastase and cathepsin G. Biol Chem Hoppe Seyler 1994; 375:659-666.
11. Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley PM. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med 2008; 178:332-338.
12. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359:1543-1554.
13. Vestbo J, Anderson JA, Calverley PM, Celli B, Ferguson GT, Jenkins C, Yates JC, Jones PW. Bias due to withdrawal in longterm randomised trials in COPD: evidence from the TORCH study. Clin Respir J 2011; 5:44-49.
14. Stockley RA, Snell N, Perrett J, Gunawardena K. Effi cacy and safety of AZD9668, an oral neutrophil elastase inhibitor, in idiopathic bronchiectasis. Eur Respir J 2010; 38s.
15. Elborn JS, Perrett J, Forsman-Semb K, Marks-Konczalik J, Gunawardena K, Entwistle N. Effect of the oral neutrophil elastase inhibitor, AZD9668, in patients with cystic fi brosis. Abstract presented at the 107th Annual Conference of the American Thoracic Society, Denver, Colorado; May 13-18, 2011.
16. Johnson D, Travis J. The oxidative inactivation of human alpha-1-proteinase inhibitor. Further evidence for methionine at the reactive center. J Biol Chem 1979; 254:4022-4026.
17. Zeiher BG, Matsuoka S, Kawabata K, Repine JE. Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics. Crit Care Med 2002; 30:S281-S287. (Pubitemid 34508004)
18. Halpin DM, Tashkin DP. Defi ning disease modifi cation in chronic obstructive pulmonary disease. COPD 2009; 6:211-225.
19. Vestbo J, Rennard S. Chronic obstructive pulmonary disease biomarker(s) for disease activity needed-urgently. Am J Respir Crit Care Med 2010; 182:863-864.
20. Franciosi LG, Page CP, Celli BR, Cazzola M, Walker MJ, Danhof M, Rabe KF, la Pasqua OE. Markers of disease severity in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2006; 19:189-199.
21. Carter RI, Mumford RA, Treonze KM, Finke PE, Davies P, Si Q, Humes JL, Dirksen A, Piitulainen E, Ahmad A, Stockley RA. Thefi brinogen cleavage product Aa-VAL360, a specifi c marker of neutrophil elastase activity in vivo. Thorax 2011; 66:686-691.
22. Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, MacNee W, Make BJ, Rabe KF, Rennard SI, Sciurba FC, Silverman EK, Vestbo J, Washko GR, Wouters EF, Martinez FJ. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010; 182:598-604.
23. From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2010. Available from: http://www.ginasthma.org/ (accessed 22 December, 2011).