Evaluation of losmapimod in patients with chronic obstructive pulmonary disease (COPD) with systemic inflammation stratified using fibrinogen ('EVOLUTION'): RATIONALE and protocol

M. Fisk, D. Mohan, J. Cheriyan*, L. Yang, J. Fuld, C. M. McEniery, R. Tal-Singer, M. I. Polkey, I. B. Wilkinson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 >2.8g/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.

Original languageEnglish
Pages (from-to)24-34
Number of pages11
JournalArtery Research
Volume8
Issue number1
DOIs
Publication statusPublished - Mar 2014
Externally publishedYes

Keywords

  • F-FDG PET/CT
  • COPD
  • Fibrinogen
  • Inflammation
  • Losmapimod
  • P38 MAPK inhibitor

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