Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial

Michelle L. O'Donoghue, Ruchira Glaser, Philip E. Aylward, Matthew A. Cavender, Adam Crisp, Keith A A Fox, Ian Laws, Jose L. Lopez-Sendon, P. Gabriel Steg, Pierre Theroux, Marc S. Sabatine, David A. Morrow

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 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.

LanguageEnglish
Pages622-630.e6
JournalAmerican Heart Journal
Volume169
Issue number5
DOIs
Publication statusPublished - 1 May 2015

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

O'Donoghue, M. L., Glaser, R., Aylward, P. E., Cavender, M. A., Crisp, A., Fox, K. A. A., ... Morrow, D. A. (2015). Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial. American Heart Journal, 169(5), 622-630.e6. https://doi.org/10.1016/j.ahj.2015.02.012
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. / Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial. In: American Heart Journal. 2015 ; Vol. 169, No. 5. pp. 622-630.e6.
@article{1ecd7d90df6f46a89c475d525b292752,
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. 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.",
author = "O'Donoghue, {Michelle L.} and Ruchira Glaser and Aylward, {Philip E.} and Cavender, {Matthew A.} and Adam Crisp and Fox, {Keith A A} and Ian Laws and Lopez-Sendon, {Jose L.} and Steg, {P. Gabriel} and Pierre Theroux and Sabatine, {Marc S.} and Morrow, {David A.}",
year = "2015",
month = "5",
day = "1",
doi = "10.1016/j.ahj.2015.02.012",
language = "English",
volume = "169",
pages = "622--630.e6",
journal = "American Heart Journal",
issn = "0002-8703",
publisher = "Mosby Inc.",
number = "5",

}

O'Donoghue, ML, Glaser, R, Aylward, PE, Cavender, MA, Crisp, A, Fox, KAA, Laws, I, Lopez-Sendon, JL, Steg, PG, Theroux, P, Sabatine, MS & Morrow, DA 2015, 'Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial', American Heart Journal, vol. 169, no. 5, pp. 622-630.e6. https://doi.org/10.1016/j.ahj.2015.02.012

Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial. / 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.

In: American Heart Journal, Vol. 169, No. 5, 01.05.2015, p. 622-630.e6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial

AU - O'Donoghue, Michelle L.

AU - Glaser, Ruchira

AU - Aylward, Philip E.

AU - Cavender, Matthew A.

AU - Crisp, Adam

AU - Fox, Keith A A

AU - Laws, Ian

AU - Lopez-Sendon, Jose L.

AU - Steg, P. Gabriel

AU - Theroux, Pierre

AU - Sabatine, Marc S.

AU - Morrow, David A.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84929278429&partnerID=8YFLogxK

U2 - 10.1016/j.ahj.2015.02.012

DO - 10.1016/j.ahj.2015.02.012

M3 - Article

VL - 169

SP - 622-630.e6

JO - American Heart Journal

T2 - American Heart Journal

JF - American Heart Journal

SN - 0002-8703

IS - 5

ER -