O'Donoghue Michelle L, Glaser Ruchira, Aylward Philip E, Cavender Matthew A, Crisp Adam, Fox Keith A A, Laws Ian, Lopez-Sendon Jose L, Steg P Gabriel, Theroux Pierre, Sabatine Marc S, Morrow David A
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
GlaxoSmithKline Pharmaceuticals, King of Prussia, PA.
Am Heart J. 2015 May;169(5):622-630.e6. doi: 10.1016/j.ahj.2015.02.012. Epub 2015 Feb 23.
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.
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.
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.
p38丝裂原活化蛋白激酶（MAPK）介导细胞因子的产生以及炎症级联反应的放大。通过抑制p38 MAPK，洛索洛芬似乎可以减轻血管壁的炎症反应，从而可能有助于稳定斑块。
LATITUDE-TIMI 60试验是一项随机、双盲、安慰剂对照、平行组、多中心研究，计划采用三阶段设计进行。总体而言，该试验旨在纳入25500例因非ST段抬高型或ST段抬高型心肌梗死（MI）住院的患者，随机分为口服洛索洛芬（7.5毫克，每日两次）组和匹配的安慰剂组。A部分包括一个先导队列（n = 3500），在进入B部分之前将对安全性和探索性疗效进行初步评估。研究的B部分（n = ~22000）由事件驱动，将对疗效进行主要评估。在B1部分的3500例患者之后将进行独立的安全性审查，以确定是否可以实施更有针对性的门诊就诊和实验室评估计划（B2部分）。所有患者均接受研究药物治疗至第12周，并随访至第24周。主要终点是心血管死亡、心肌梗死或需要紧急冠状动脉血运重建的严重复发性缺血的复合终点。关键次要终点是心血管死亡或心肌梗死的复合终点。该试验旨在为主要终点提供≥90%的检验效能。
LATITUDE-TIMI 60试验将确定在急性心肌梗死中使用洛索洛芬短期抑制p-38 MAPK的疗效和安全性。该试验设计采用逐步决策和数据收集方法。
