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Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.
MedLine Citation:
PMID:  24930728     Owner:  NLM     Status:  Publisher    
BACKGROUND: p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial.
METHODS: From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with, number NCT00910962.
FINDINGS: Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ.
INTERPRETATION: p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes.
FUNDING: GlaxoSmithKline.
L Kristin Newby; Michael S Marber; Chiara Melloni; Lea Sarov-Blat; Laura H Aberle; Philip E Aylward; Gengqian Cai; Robbert J de Winter; Christian W Hamm; John F Heitner; Raymond Kim; Amir Lerman; Manesh R Patel; Jean-Francois Tanguay; John J Lepore; Hussein R Al-Khalidi; Dennis L Sprecher; Christopher B Granger;
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-6-12
Journal Detail:
Title:  Lancet     Volume:  -     ISSN:  1474-547X     ISO Abbreviation:  Lancet     Publication Date:  2014 Jun 
Date Detail:
Created Date:  2014-6-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985213R     Medline TA:  Lancet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 Elsevier Ltd. All rights reserved.
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