A Clinical Outcomes Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting with Acute Coronary Syndrome Treated with Losmapimod Compared to Placebo (PM1116197, LATITUDE STUDY)
(Short title: LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE (LATITUDE)-TIMI 60)

p38 mitogen-activated protein kinase (MAPK) is an important mediator of
inflammation that leads to activation of cytokine production during acute
coronary syndrome (ACS). Evidence suggests that p38 MAPK inhibition may
potentially interrupt the inflammatory processes in the vascular wall, thus
stabilizing atherosclerotic plaques, and reducing the risk of subsequent plaque
rupture.
Losmapimod is a selective inhibitor of p38 MAPK. It is being developed in
several indications, e.g. COPD and ACS. The safety of losmapimod for 12 weeks,
and its effects on systemic inflammation, infarct size and cardiac function was
evaluated in a Phase II placebo-controlled study in 526 subjects with
non-ST-segment elevation myocardial infarction (NSTEMI). Acute increases in
inflammatory biomarkers during the in-hospital period were significantly
attenuated on losmapimod versus placebo. Although the trial was not powered to
assess clinical outcomes, there was a non-significant trend toward lower
incidence of major adverse cardiovascular events (MACE) compared to placebo,
which was driven by a reduction in myocardial infarction. A subgroup of
subjects who underwent cardiac MRI had statistically significant improvements
in left ventricular ejection fraction and left ventricular volumes at Week 12
versus placebo.
This Phase III trial will compare the effects of losmapimod for 12 weeks versus
placebo when added to standard of care on the incidence of MACE in subjects
with ACS (NSTEMI and STEMI).

Primary: To evaluate the efficacy of oral losmapimod compared to placebo added
to standard of care in subjects with ACS on the time to first occurrence of
adjudicated MACE (defined as CV death, MI, or severe recurrent ischemia
requiring urgent coronary artery revascularization through 12 weeks of therapy.
Principal secondary: to evaluate the efficacy of losmapimod on the time to
first occurrence of adjudicated CV death or MI.

Multicenter randomized double blind phase III parallel group study.
Randomization 1:1 to:
* Oral losmapimod 7.5mg BID
* Placebo.
On top of standard care.
Treatment period 12 weeks, follow-up period 12 weeks.
The study has3 parts.
Part A: Subjects will be randomized to provide an initial assessment of safety
and exploratory efficacy (~200 reports of primary endpoint events) before
progressing to Part B1. Efficacy data from Part A of the study will not be used
in the primary efficacy analysis of the trial.
Upon completion of treatment of Part A, summary level unblinded efficacy and
safety data from Part A will be reviewed by a limited group involved in study
conduct, who will make a decision on whether or not to proceed to Part B1.
Continuation needs endorsement from the IDMC. It is expected that the protocol
will not bemodified when progressing from part A to part B1. A decision to
proceed to Part B2 can only be made with endorsement with respect to safety
from the IDMC. This review will occur prior to initiation of recruitment in
Part B2.
Part B: will be event driven to provide the main assessment of efficacy with an
event target of 1,400 adjudicated primary endpoint events, and 1,000*1,200
adjudicated CV death/MI.
25.500 patients (3.500 in part A and part B1 each and 18.500 in part B2). NL:
870 (170 in part A, 700 in B).
NB: For question C9 (participating centers and nr. of pats) for NL the data for
part A have been entered. For part B additional centers will be added in due
time and the total number of pats per center will be fixed.
Independent Data Monitoring Committee.

Treatment with losmapimod or placebo.

Risk: Adverse effects of study medication.
Burden:
3 visits after hospital discharge (in part B2 possibly 1 visit and 2 telephone
calls). Hospital stay not prolonged by study.
After discharge: 2 (in B2 possibly 1) times physical examination and 2 (in B2
possibly 1) times ECG.
In total max 6 (in B2 possibly 4) blood draws for study purposes (5-50
ml/occasion) plus 3 (in B2 possibly 2) times pregnancy test.
Renal substudy (optional): 2 extra visits after discharge from hospital. In
total 2 extra blood draws for study purposes.