title: Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial.
abstract: BACKGROUND
  p38 mitogen-activated protein kinase (MAPK) mediates cytokine production and amplification of the inflammatory cascade. Through inhibition of p38 MAPK, losmapimod appears to attenuate the inflammatory response in the vascular wall and thus may help stabilize plaques.
  
  
  METHODS
  The LATITUDE-TIMI 60 trial is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study planned to be conducted in a 3-stage design. Overall, the trial is designed to include 25,500 patients hospitalized with non-ST-elevation or ST-elevation myocardial infarction (MI) randomized to oral losmapimod (7.5 mg twice daily) versus matching placebo. Part A consists of a leading cohort (n = 3,500) that will provide an initial assessment of safety and exploratory efficacy before progressing to part B. Part B (n = ~22,000) of the study is event driven and will provide the primary assessment of efficacy. An independent safety review will be conducted after 3,500 patients in part B1 to determine whether a more focused schedule of clinic visits and laboratory assessments can be implemented (part B2). All patients are to be treated with study drug until week 12 and followed up until week 24. The primary end point is the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization. The key secondary end point is the composite of cardiovascular death or MI. The trial is designed to provide ≥90% power for the primary end point.
  
  
  CONCLUSIONS
  The LATITUDE-TIMI 60 trial will determine the efficacy and safety of short-term p38 MAPK inhibition with losmapimod in acute MI. The trial design adopts a stepwise approach to decision making and collection of data.
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: O'Donoghue
authors.affiliation: GlaxoSmithKline Pharmaceuticals, King of Prussia, PA.
authors.forename: Ruchira
authors.initials: R
authors.lastname: Glaser
authors.affiliation: South Australian Health and Medical Research Institute, Flinders University Medical Centre, Adelaide, SA, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cavender
authors.affiliation: GlaxoSmithKline Pharmaceuticals, King of Prussia, PA.
authors.forename: Adam
authors.initials: A
authors.lastname: Crisp
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.affiliation: GlaxoSmithKline Pharmaceuticals, King of Prussia, PA.
authors.forename: Ian
authors.initials: I
authors.lastname: Laws
authors.affiliation: Cardiovascular Division, University Hospital La Paz, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lopez-Sendon
authors.affiliation: FACT, DHU FIRE, Université Paris-Diderot, Sorbonne Paris-Cité; NHLI, Imperial College, Royal Brompton Hospital, London, UK.
authors.forename: P Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: From the Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Theroux
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000328:Adult; D003521:Cyclopropanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D012107:Research Design; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases