Artery Research

Volume 8, Issue 1, March 2014, Pages 24 - 34

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

Authors
M. Fiska, f, D. Mohanb, f, J. Cheriyana, e, *, f, L. Yanga, J. Fuldc, C.M. McEnierya, R. Tal-Singerd, M.I. Polkeyb, I.B. Wilkinsona, e
aCambridge University Hospitals NHS Foundation Trust & Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom
bNIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Trust and Imperial College, London, United Kingdom
cDepartment of Respiratory Medicine, Cambridge University Hospitals NHS Foundation Trust, United Kingdom
dGlaxoSmithKline, King of Prussia, PA, USA
eCambridge Clinical Trials Unit, Cambridge, United Kingdom
f

Joint first authors.

*Corresponding author. Box 110, Level 3, ACCI Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom. Tel.: +44 1223 296070; fax: +44 1223 296006. E-mail address: jc403@cam.ac.uk (J. Cheriyan).
Corresponding Author
J. Cheriyan
Received 12 September 2013, Accepted 1 October 2013, Available Online 8 November 2013.
DOI
https://doi.org/10.1016/j.artres.2013.10.380How to use a DOI?
Keywords
COPD, Losmapimod, p38 MAPK inhibitor, Fibrinogen, Inflammation, 18F-FDG PET/CT
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.

Copyright
© 2013 Association for Research into Arterial Structure and Physiology. Published by Elsevier B.V. All rights reserved.
Open Access
This is an open access article distributed under the CC BY-NC license.

Download article (PDF)
View full text (HTML)

Journal
Artery Research
Volume-Issue
8 - 1
Pages
24 - 34
Publication Date
2013/11
ISSN (Online)
1876-4401
ISSN (Print)
1872-9312
DOI
https://doi.org/10.1016/j.artres.2013.10.380How to use a DOI?
Copyright
© 2013 Association for Research into Arterial Structure and Physiology. Published by Elsevier B.V. All rights reserved.
Open Access
This is an open access article distributed under the CC BY-NC license.

Cite this article

TY  - JOUR
AU  - M. Fisk
AU  - D. Mohan
AU  - J. Cheriyan
AU  - L. Yang
AU  - J. Fuld
AU  - C.M. McEniery
AU  - R. Tal-Singer
AU  - M.I. Polkey
AU  - I.B. Wilkinson
PY  - 2013
DA  - 2013/11
TI  - Evaluation of losmapimod in patients with chronic obstructive pulmonary disease (COPD) with systemic inflammation stratified using fibrinogen (‘EVOLUTION’): Rationale and protocol
JO  - Artery Research
SP  - 24
EP  - 34
VL  - 8
IS  - 1
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2013.10.380
DO  - https://doi.org/10.1016/j.artres.2013.10.380
ID  - Fisk2013
ER  -