Michelle L O'Donoghue1, Ruchira Glaser2, Philip E Aylward3, Matthew A Cavender1, Adam Crisp2, Keith A A Fox4, Ian Laws2, Jose L Lopez-Sendon5, P Gabriel Steg6, Pierre Theroux7, Marc S Sabatine1, David A Morrow1. 1. TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA. 2. GlaxoSmithKline Pharmaceuticals, King of Prussia, PA. 3. South Australian Health and Medical Research Institute, Flinders University Medical Centre, Adelaide, SA, Australia. 4. Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. 5. Cardiovascular Division, University Hospital La Paz, Madrid, Spain. 6. FACT, DHU FIRE, Université Paris-Diderot, Sorbonne Paris-Cité; NHLI, Imperial College, Royal Brompton Hospital, London, UK. 7. From the Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
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. STUDY DESIGN: 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 tooral 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.
RCT Entities:
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. STUDY DESIGN: 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: Jesús García-Cano; Olga Roche; Francisco J Cimas; Raquel Pascual-Serra; Marta Ortega-Muelas; Diego M Fernández-Aroca; Ricardo Sánchez-Prieto Journal: Front Cell Dev Biol Date: 2016-06-30