NCT02145468: LATITUDE

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)

Completed Phase 3 Results posted Last updated 2 June 2017

What this trial tests

Phase 3 trial testing Losmapimod 7.5 mg twice daily in Acute Coronary Syndrome in 3,503 participants. Completed in 14 December 2015.

Timeline

3 June 2014

Primary endpoint
14 December 2015

14 December 2015

Quick facts

Lead sponsor	GlaxoSmithKline
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	3,503
Start date	3 June 2014
Primary completion	14 December 2015
Estimated completion	14 December 2015
Sites	341 locations across Hong Kong, Italy, Taiwan, Poland, South Korea, Philippines, Denmark, New Zealand

Drugs / interventions tested

• Losmapimod 7.5 mg twice daily — full drug profile →
• Placebo twice daily
• Standard therapy — full drug profile →

Conditions studied

• Acute Coronary Syndrome — all drugs for Acute Coronary Syndrome →

Sponsor

GlaxoSmithKline — full company profile →

Who can join

35 and older, any sex, with Acute Coronary Syndrome. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With First Occurrence of Major Adverse Cardiovascular Events (MACE) Through Week 12 Primary · Up to 12 weeks

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.

First occurence of MACE

Group	Value	95% CI
Placebo	123
Losmapimod 7.5 mg BID	139

CV Death

Group	Value	95% CI
Placebo	34
Losmapimod 7.5 mg BID	31

MI

Group	Value	95% CI
Placebo	74
Losmapimod 7.5 mg BID	90

SRI-UR

Group	Value	95% CI
Placebo	15
Losmapimod 7.5 mg BID	18

Number of Participants With First Occurrence of MACE Through Week 24 Secondary · Up to 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.

First occurrence of MACE

Group	Value	95% CI
Placebo	162
Losmapimod 7.5 mg BID	176

CV Death

Group	Value	95% CI
Placebo	45
Losmapimod 7.5 mg BID	38

MI

Group	Value	95% CI
Placebo	98
Losmapimod 7.5 mg BID	117

SRI-UR

Group	Value	95% CI
Placebo	19
Losmapimod 7.5 mg BID	21

Number of Participants With First Occurrence of the Composite of CV Death or MI up to Week 12 and Week 24 Secondary · 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

Group	Value	95% CI
Placebo	110
Losmapimod 7.5 mg BID	122

Week 24

Group	Value	95% CI
Placebo	145
Losmapimod 7.5 mg BID	156

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. Secondary · 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

Group	Value	95% CI
Placebo	131
Losmapimod 7.5 mg BID	140

Week 24

Group	Value	95% CI
Placebo	169
Losmapimod 7.5 mg BID	178

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 Secondary · Week 12, 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

Group	Value	95% CI
Placebo	135
Losmapimod 7.5 mg BID	151

Week 24

Group	Value	95% CI
Placebo	174
Losmapimod 7.5 mg BID	190

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 Secondary · Week 12, 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

Group	Value	95% CI
Placebo	144
Losmapimod 7.5 mg BID	152

Week 24

Group	Value	95% CI
Placebo	186
Losmapimod 7.5 mg BID	194

Number of Participants With First Occurrence of the Composite of CV Death or Hospitalization for HF Through to Week 12 and Week 24 Secondary · 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 are presented.

Week 12

Group	Value	95% CI
Placebo	72
Losmapimod 7.5 mg BID	64

Week 24

Group	Value	95% CI
Placebo	94
Losmapimod 7.5 mg BID	86

Number of Participants With First Occurrence of the Composite of CV Death, MI or Stroke Through to Week 12 and Week 24 Secondary · 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 are presented.

Week 12

Group	Value	95% CI
Placebo	122
Losmapimod 7.5 mg BID	134

Week 24

Group	Value	95% CI
Placebo	157
Losmapimod 7.5 mg BID	170

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 Secondary · 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 are presented.

Week 12

Group	Value	95% CI
Placebo	155
Losmapimod 7.5 mg BID	169

Week 24

Group	Value	95% CI
Placebo	197
Losmapimod 7.5 mg BID	212

Number of Participants With First Occurrence of the Composite of CHD Death, MI or SRI-UR Through to Week 12 and Week 24 Secondary · 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 are presented.

Week 12

Group	Value	95% CI
Placebo	119
Losmapimod 7.5 mg BID	133

Week 24

Group	Value	95% CI
Placebo	152
Losmapimod 7.5 mg BID	167

Number of Participants With First Occurrence of the Composite of CHD Death or MI Through to Week 12 and Week 24 Secondary · 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 are presented.

Week 12

Group	Value	95% CI
Placebo	106
Losmapimod 7.5 mg BID	116

Week 24

Group	Value	95% CI
Placebo	135
Losmapimod 7.5 mg BID	147

Number of Participants With First Occurrence of the Composite of All-cause Death, MI or SRI-UR Through to Week 12 and Week 24 Secondary · 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 are presented.

Week 12

Group	Value	95% CI
Placebo	128
Losmapimod 7.5 mg BID	142

Week 24

Group	Value	95% CI
Placebo	169
Losmapimod 7.5 mg BID	185

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until follow-up (up to Week 24). Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 323/1752 (18%)

Deaths: 68/1752

Losmapimod 7.5 mg BID

Serious: 363/1724 (21%)

Deaths: 57/1724

Serious adverse events (393 terms)

Reaction	System	Placebo	Losmapimod 7.5 mg BID
Angina unstable	Cardiac disorders	—	—
Angina pectoris	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Non-cardiac chest pain	General disorders	—	—
Pneumonia	Infections and infestations	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Troponin increased	Investigations	—	—
Cardiac failure	Cardiac disorders	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Ventricular fibrillation	Cardiac disorders	—	—
Ventricular tachycardia	Cardiac disorders	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Cardiac procedure complication	Injury, poisoning and procedural complications	—	—
Cardiogenic shock	Cardiac disorders	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—
Chronic kidney disease	Renal and urinary disorders	—	—
Peripheral ischaemia	Vascular disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Chest pain	General disorders	—	—
Hypotension	Vascular disorders	—	—
Syncope	Nervous system disorders	—	—

Other adverse events (11 terms — click to expand)

Reaction	System	Placebo	Losmapimod 7.5 mg BID
Atrial fibrillation	Cardiac disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Hypertension	Vascular disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Non-cardiac chest pain	General disorders	—	—
Angina pectoris	Cardiac disorders	—	—
Troponin increased	Investigations	—	—
Anemia	Blood and lymphatic system disorders	—	—
Dizziness	Nervous system disorders	—	—
Hypotension	Vascular disorders	—	—

Most-reported serious reactions: Angina unstable, Angina pectoris, Atrial fibrillation, Non-cardiac chest pain, Pneumonia, Musculoskeletal chest pain, Acute myocardial infarction, Acute kidney injury.

Data from ClinicalTrials.gov NCT02145468 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention.
   Kong P, Cui ZY, Huang XF, Zhang DD, et al · · 2022 · cited 749× · PMID 35459215 · DOI 10.1038/s41392-022-00955-7
2. Targeting inflammation in atherosclerosis - from experimental insights to the clinic.
   Soehnlein O, Libby P. · · 2021 · cited 723× · PMID 33976384 · DOI 10.1038/s41573-021-00198-1
3. Signaling pathways and targeted therapy for myocardial infarction.
   Zhang Q, Wang L, Wang S, Cheng H, et al · · 2022 · cited 525× · PMID 35273164 · DOI 10.1038/s41392-022-00925-z
4. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial.
   O'Donoghue ML, Glaser R, Cavender MA, Aylward PE, et al · · 2016 · cited 192× · PMID 27043082 · DOI 10.1001/jama.2016.3609
5. Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets.
   Chen R, Zhang H, Tang B, Luo Y, et al · · 2024 · cited 169× · PMID 38816371 · DOI 10.1038/s41392-024-01840-1
6. An overview of mammalian p38 mitogen-activated protein kinases, central regulators of cell stress and receptor signaling.
   Han J, Wu J, Silke J. · · 2020 · cited 103× · PMID 32612808 · DOI 10.12688/f1000research.22092.1
7. p38 MAPK in cardioprotection - are we there yet?
   Martin ED, Bassi R, Marber MS. · · 2015 · cited 54× · PMID 25204838 · DOI 10.1111/bph.12901
8. Atypical p38 Signaling, Activation, and Implications for Disease.
   Burton JC, Antoniades W, Okalova J, Roos MM, et al · · 2021 · cited 52× · PMID 33920735 · DOI 10.3390/ijms22084183