A Phase 3 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 (LATITUDE-TIMI 60)

Study Overview
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Brief Summary
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Losmapimod is a new anti-inflammatory medication which potentially may benefit patients with Acute Coronary Syndrome, (ACS), a condition which includes heart attack. There is a growing understanding that the inflammatory response to ACS is integral to the subsequent evolution of plaque instability. Losmapimod inhibits p38 mitogen activated protein kinase (MAPK), an enzyme which may play a central role in inflammation in the setting of heart attack. Inhibition of p38 MAPK may stabilize atherosclerotic plaques, reduce the risk of subsequent plaque rupture, indirectly improve vascular function and prevent subsequent thrombosis, and thus reduce infarct size and the risk of subsequent cardiac events. This study will test whether losmapimod can safely reduce the risk of a subsequent cardiovascular event (such as death, heart attack, or near heart attack requiring urgent treatment ) when started immediately after ACS (specifically, heart attack). Patients who present with heart attack and qualify for the study will be randomly assigned to receive 3 months treatment with either losmapimod twice daily or placebo, which will be administered in addition to the usual standard of care therapies for heart attack. Following the in-hospital period, subjects will return for outpatient visits at 4 and 12 weeks, as well as a follow up visit at 24 weeks.

Official Title
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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) LosmApimod To Inhibit p38 MAP Kinase as a TherapeUtic Target and moDify Outcomes After an Acute Coronary syndromE (LATITUDE)-TIMI 60.

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Losmapimod 7.5 mg twice daily
* Drug: Placebo twice daily
* Drug: Standard therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Men or women at least 35 years old. Women must be post-menopausal or using a highly effective method for avoidance of pregnancy Hospitalization for NSTEMI or STEMI (Universal Definition Type 1 MI) With the following timing of symptoms: NSTEMI: Presence of ischemic symptoms (>=5 minutes) at rest within 24 hours prior to randomization (may include qualifying episode). STEMI: Onset of qualifying ischemic symptoms within 12 hours of randomization. At least one of the following Age >=60 years at randomization. Myocardial infarction prior to the qualifying ACS event CABG prior to qualifying ACS event. NSTEMI with new ischemic ST-segment depression >= 0.1 mV in >= 2 contiguous leads. Diabetes mellitus requiring pharmacotherapy. Coexistent clinically diagnosed arterial disease Exclusion Criteria: Unable to be randomized prior to coronary revascularization or fibrinolysis for the qualifying MI. Current severe heart failure or shock Ongoing clinical instability History of chronic liver disease Known severe renal impairment Any condition, other than vascular disease, with life expectancy <1 year that might prevent the subject from completing the study. Known active tuberculosis, HIV, active opportunistic or life threatening infections. Vaccination with a live attenuated vaccine within 6 weeks of randomization. Concomitant use of cytotoxic chemotherapy for cancer or known ongoing or anticipated use of chronic severe immunosuppressive agents Positive pregnancy test or is known to be pregnant or lactating Known alcohol or drug abuse within the past 6 months Any current mental condition, which may affect study compliance or prevent understanding of the aims, investigational procedures or possible consequences of the study. Participation in a study of an investigational medication within the past 30 days. Anticipated inability to comply with any study procedures, including participation in study visits according to the visit schedule through 24 weeks. Use of another investigational product within 30 days or 5 half-lives (whichever is longer) or according to local regulations, or currently participating in a study of an investigational device. Subjects must be randomized only one time in this investigational study Any other reason the investigator deems the subject to be unsuitable for the study

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losmapimod<br>Losmapimod 7.5 mg twice daily oral tablet | Drug: Losmapimod 7.5 mg twice daily<br>* Subjects will receive Losmapimod 7.5 mg as film-coated, round, plain faced tablets.<br>* Other names: GW856553;Drug: Standard therapy<br>* Subjects will receive standard therapy consistent with the appropriate guidelines from professional societies. The standard therapy includes nitrates, morphine sulfate, beta adrenergic blockers, renin-angiotensin aldosterone inhibitors, other anti-ischemic therapies, and analgesic therapy.<br>|
| Placebo Comparator: Placebo<br>Placebo twice daily oral tablet | Drug: Placebo twice daily<br>* Subjects will receive placebo as film-coated, round, plain faced tablets.<br>Drug: Standard therapy<br>* Subjects will receive standard therapy consistent with the appropriate guidelines from professional societies. The standard therapy includes nitrates, morphine sulfate, beta adrenergic blockers, renin-angiotensin aldosterone inhibitors, other anti-ischemic therapies, and analgesic therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of Major Adverse Cardiovascular Events (MACE) Through Week 12 | The primary efficacy endpoint is the composite measure of adjudicated MACE that includes the time to first occurrence of CV death (death due to a cardiovascular cause), MI or SRI-UR (Severe Recurrent Ischemia requiring Urgent coronary artery Revascularization). Death for which the Clinical Events Committee (CEC) or investigator were unable to establish cause were analyzed as CV deaths. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of the Expanded Composite of Arterial CV Events Defined as CV Death, MI, SRI-UR or Stroke Through to Week 12 and Week 24 | Number of participants with first occurrence of the expanded composite of arterial CV events defined as CV death, MI, SRI-UR or stroke through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of Coronary Events Defined as CHD Death, MI, SRI-UR or Any Unplanned Coronary Artery Revascularization Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of coronary events defined as coronary heart disease (CHD) death, MI, SRI-UR or any unplanned coronary artery revascularization through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of CV Death or Hospitalization for HF Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of CV death or hospitalization for HF through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of CV Death, MI or Stroke Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of CV death, MI or stroke through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Expanded Composite of CV Death, MI, SRI-UR, Stroke or Hospitalization for HF Through to Week 12 and Week 24 | Number of participants with first occurrence of the expanded composite of CV death, MI, SRI-UR, stroke or hospitalization for HF through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of CHD Death, MI or SRI-UR Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of CHD death, MI or SRI-UR through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of CHD Death or MI Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of CHD death or MI through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of All-cause Death, MI or SRI-UR Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of all-cause death, MI or SRI-UR through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of All-cause Death or MI Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of all-cause death or MI through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of CV Death, Type I (Spontaneous) MI or SRI-UR Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of CV death, type I (spontaneous) MI or SRI-UR through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of the Composite of CV Death or Type I (Spontaneous) MI Through to Week 12 and Week 24 | Number of participants with first occurrence of the composite of CV death or type I (spontaneous) MI through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of Definite or Probable Stent Thrombosis Through to Week 12 and Week 24 | Number of participants with first occurrence of definite or probable stent thrombosis through to Week 12 and Week 24 are presented. Participants receiving stent prior to randomization or during the study prior to Week 12 were included. | Week 12, Week 24 | 
| Number of Participants Re-hospitalized Within 30 Days of Discharge | Participants who had a death or re-hospitalization within 30 days of discharge, plus participants who were never discharged from the initial hospitalization were included. | Within up to 30 days of post discharge | 
| Number of Participants With All-cause Mortality Through to Week 12 and Week 24 | Number of participants with all-cause mortality through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With CV Death Events Through to Week 12 and Week 24 | Number of participants with CV death events through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With CHD Death Events Through to Week 12 and Week 24 | Number of participants with CHD death events through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of Myocardial Infarction (Fatal and Non-fatal) Events Through to Week 12 and Week 24 | Number of participants with first occurrence of myocardial infarction (fatal and non-fatal) events through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of Type I (Spontaneous) MI Events Through to Week 12 and Week 24 | Number of participants with first occurrence of type I (spontaneous) MI events through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of SRI-UR Events Through to Week 12 and Week 24 | Number of participants with first occurrence of SRI-UR events through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of Stroke (Fatal and Non-fatal) Events Through to Week 12 and Week 24 | Number of participants with first occurrence of stroke (fatal and non-fatal) events through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of Hospitalization for HF Through to Week 12 and Week 24 | Number of participants with first occurrence of hospitalization for HF through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of Any Unplanned Coronary Revascularization Through to Week 12 and Week 24 | Number of participants with first occurrence of any unplanned coronary revascularization through to Week 12 and Week 24 are presented. | Week 12, Week 24 | 
| Number of Participants With First Occurrence of MACE Through Week 24 | Number of participants with first occurrence of MACE through Week 24 including CV death, MI or SRI-UR are presented. Death for which the CEC or investigator were unable to establish cause were analyzed as CV deaths. | Up to Week 24 | 
| Number of Participants With First Occurrence of the Composite of CV Death or MI up to Week 12 and Week 24 | Week 12 results are considered the principal secondary endpoint. Number of participants with first occurrence of the composite of CV death or MI up to Week 12 and Week 24 are summarized. | Week 12 and Week 24 | 
| Number of Participants With First Occurrence of the Composite of CV Death, MI or Hospitalization for Heart Failure (HF) up to Week 12 and Week 24. | Number of participants with first occurrence of the composite of CV death, MI or hospitalization for HF up to Week 12 and Week 24 are presented. | Week 12 and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial infarction, Acute coronary syndrome, Cardiovascular disease, p38 mitogen-activated protein kinase (MAPK) inhibitor, NSTEMI, Losmapimod, STEMI