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

doi:10.1016/j.artres.2013.10.380

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

Authors

M. Fisk^a^{, f}, D. Mohan^b^{, f}, J. Cheriyan^a^{, e}^{, *}^{, f}, L. Yang^a, J. Fuld^c, C.M. McEniery^a, R. Tal-Singer^d, M.I. Polkey^b, I.B. Wilkinson^a^{, 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: 10.1016/j.artres.2013.10.380 How 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.
Open Access: This is an open access article distributed under the CC BY-NC license.

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<Previous Article In Issue

Journal: Artery Research
Volume-Issue: 8 - 1
Pages: 24 - 34
Publication Date: 2013/11/08
ISSN (Online): 1876-4401
ISSN (Print): 1872-9312
DOI: 10.1016/j.artres.2013.10.380 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC license.

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ris enw bib

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  - 2013/11/08
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  - 10.1016/j.artres.2013.10.380
ID  - Fisk2013
ER  -

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