Abstract 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 >2.8 g/L. Methods Patients are randomised to 7.5 mg 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.