TY - JOUR
T1 - Evaluation of losmapimod in patients with chronic obstructive pulmonary disease (COPD) with systemic inflammation stratified using fibrinogen ('EVOLUTION')
T2 - RATIONALE and protocol
AU - Fisk, M.
AU - Mohan, D.
AU - Cheriyan, J.
AU - Yang, L.
AU - Fuld, J.
AU - McEniery, C. M.
AU - Tal-Singer, R.
AU - Polkey, M. I.
AU - Wilkinson, I. B.
PY - 2014/3
Y1 - 2014/3
N2 - Introduction: p38 mitogen-activated protein kinases (MAPK) are key signalling molecules in cellular responses to external stresses, regulate pro-inflammatory cytokine expression and are implicated in the inflammatory pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. The EVOLUTION trial is a randomised, double-blind, placebo-controlled, Phase 2a trial recruiting from two UK centres that aims to evaluate the effects of Losmapimod (GW856553), a potent oral p38α/β MAPK inhibitor in COPD patients stratified by a fibrinogen level >2.8g/L. Methods: Patients are randomised to 7.5mg losmapimod or matching placebo tablets twice daily for four months. Vascular and pulmonary inflammation is assessed by 18F-FDG PET/CT at baseline and following treatment. Other endpoints including flow-mediated dilatation, aortic pulse wave velocity, spirometry, six-minute walk distance and blood biomarkers of inflammation, are evaluated pre- and post-treatment. Results: The primary endpoints following 16 weeks treatment include, 1) change in arterial inflammation measured by 18F-FDG PET/CT signal in the aorta and carotid arteries, 2) change in atheromatous plaque and aortic wall characterisation evaluated by 18F-FDG PET/CT and MRI, and 3) change in flow-mediated dilatation.Key secondary endpoints include change in 1) pulmonary inflammation evaluated by 18F-FDG PET/CT, 2) change in respiratory and physical function indices, 3) arterial stiffness, and 4) measures of systemic biomarkers. Safety endpoints include serious and non-serious adverse events, clinical laboratory results and ECGs. Discussion: Data gained from the EVOLUTION trial will provide novel information on pulmonary and extra-pulmonary effects of losmapimod in inflammatory disease, in a COPD population with evidence of systemic inflammation.
AB - Introduction: p38 mitogen-activated protein kinases (MAPK) are key signalling molecules in cellular responses to external stresses, regulate pro-inflammatory cytokine expression and are implicated in the inflammatory pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. The EVOLUTION trial is a randomised, double-blind, placebo-controlled, Phase 2a trial recruiting from two UK centres that aims to evaluate the effects of Losmapimod (GW856553), a potent oral p38α/β MAPK inhibitor in COPD patients stratified by a fibrinogen level >2.8g/L. Methods: Patients are randomised to 7.5mg losmapimod or matching placebo tablets twice daily for four months. Vascular and pulmonary inflammation is assessed by 18F-FDG PET/CT at baseline and following treatment. Other endpoints including flow-mediated dilatation, aortic pulse wave velocity, spirometry, six-minute walk distance and blood biomarkers of inflammation, are evaluated pre- and post-treatment. Results: The primary endpoints following 16 weeks treatment include, 1) change in arterial inflammation measured by 18F-FDG PET/CT signal in the aorta and carotid arteries, 2) change in atheromatous plaque and aortic wall characterisation evaluated by 18F-FDG PET/CT and MRI, and 3) change in flow-mediated dilatation.Key secondary endpoints include change in 1) pulmonary inflammation evaluated by 18F-FDG PET/CT, 2) change in respiratory and physical function indices, 3) arterial stiffness, and 4) measures of systemic biomarkers. Safety endpoints include serious and non-serious adverse events, clinical laboratory results and ECGs. Discussion: Data gained from the EVOLUTION trial will provide novel information on pulmonary and extra-pulmonary effects of losmapimod in inflammatory disease, in a COPD population with evidence of systemic inflammation.
KW - F-FDG PET/CT
KW - COPD
KW - Fibrinogen
KW - Inflammation
KW - Losmapimod
KW - P38 MAPK inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84893939067&partnerID=8YFLogxK
U2 - 10.1016/j.artres.2013.10.380
DO - 10.1016/j.artres.2013.10.380
M3 - Article
AN - SCOPUS:84893939067
SN - 1872-9312
VL - 8
SP - 24
EP - 34
JO - Artery Research
JF - Artery Research
IS - 1
ER -