MedDRA version: 16.1 Level: LLT Classification code 10003723 Term: Attack coronary System Organ Class: 10007541 - Cardiac disorders MedDRA version: 16.1 Level: PT Classification code 10051592 Term: Acute coronary syndrome System Organ Class: 10007541 - Cardiac disorders MedDRA version: 16.1 Level: LLT Classification code 10071111 Term: Non ST segment elevation acute coronary syndrome System Organ Class: 10007541 - Cardiac disorders MedDRA version: 16.1 Level: LLT Classification code 10041894
Conditions
Interventions
Product Name: Losmapimod
Product Code: GW856553
Pharmaceutical Form: Tablet
INN or Proposed INN: Losmapimod
CAS Number: 585543-15-3
Current Sponsor code: GW856553
Other descriptive name: GW 856553X
Co
Sponsors
GlaxoSmithKline Research & Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Signed written informed consent prior to beginning study-related procedures. The subject must understand the aims, investigational procedures and possible consequences of the study 2.Male or female aged 35 years or older at randomization. A female subject is eligible to participate if she is of non-child bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea or if of child-bearing potential is using a highly effective method for avoidance of pregnancy (refer to Appendix 1) for the duration of dosing and until 2 weeks post last-dose. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator and in accordance with local practice in relation to adequate contraception. 3.Hospitalization for NSTEMI or STEMI (Universal Definition Type 1 MI). NSTEMI that is presumed spontaneous (Universal Definition Type 1) and is defined as ischemic chest discomfort (or equivalent) that occurs or persists at rest with at least 1 episode lasting =10 minutes and is accompanied by a diagnostic elevation in cardiac troponin above the upper limit of normal (99th percentile decision-limit) according to the local laboratory without persistent ST segment elevation. If cardiac troponin is not available, then creatine-kinase MB isoenzyme (CK-MB) must be above the upper limit of normal. The biomarker should exhibit a rising and/or falling pattern when serial testing is available prior to randomization. STEMI is defined as ischemic chest discomfort (or equivalent) that occurs or persists at rest with ST segment elevation of at least 0.1 mV in 2 or more contiguous leads or new (or presumed new) left bundle branch block (LBBB) and a presumed diagnosis of STEMI. NOTE: Subjects with clinical or laboratory manifestations of ACS (e.g., ST-elevation or increase in cardiac enzymes) that are believed to be secondary to other apparent illness (e.g., sepsis, profound anemia, hypertensive emergency or decompensated heart failure, coronary embolism or dissection; Universal Type 2 MI) or known to be procedurally related (Type 4 - including stent thrombosis- or Type 5) are not considered to meet these criteria for NSTEMI or STEMI. 4.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. 5.All subjects must also have at least one of the following additional predictors of cardiovascular risk: a.Age =60 years at randomization. b.History of documented MI (known or presumed Type 1 MI) prior to qualifying ACS event. c.History of CABG prior to qualifying ACS event. d.NSTEMI with new ischemic ST-segment depression =0.1 mV in =2 contiguous leads. e.Diabetes mellitus requiring pharmacotherapy. f.Coexistent clinically diagnosed arterial disease in at least 1 peripheral arterial territory, defined as: •History of non-cardioembolic (known or presumed), ischemic stroke (confirmed by medical records or history) or •Current or history of peripheral arterial disease: current intermittent claudication with an ankle-brachial index =0.85 or history of peripheral arterial stenting or surgery (including amputation due to vascular causes). French subjects: In France, a subject will be eligible for inclusion in this study
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study: 1. Unable to be randomized prior to coronary revascularization or fibrinolysis for the qualifying MI. 2. Current severe heart failure or shock (New York Heart Association [NYHA] class III or IV, or Killip class III or IV). 3. Ongoing clinical instability (e.g., hypotension requiring vasopressor or inotropic support, new stroke or transient ischemic attack [TIA], or recurrent sustained ventricular tachycardia). 4. History of chronic liver disease (defined below) or known to have current ALT =2x upper limit of normal or total bilirubin >1.5x upper limit of normal or known history of hepatitis B or C. Defined as known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones). Such abnormalities include current drug therapy for the treatment of liver disease, unstable liver disease (defined by the presence of any of the following deemed by the investigator to be related to liver disease and not to other disease processes: ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice) or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study. 5.Known severe renal impairment. Severe renal impairment is defined as receiving chronic dialysis or known estimated glomerular filtration rate (eGFR) 10 mg/day for >14 consecutive days. •Currently receiving any systemic immunosuppressive therapy (See SPM for details). 10.Positive pregnancy test or is known to be pregnant or lactating. All female subjects of childbearing potential must have a urine or serum ß-human chorionic gonadotropin [hCG] pregnancy test performed prior to randomization. 11.Known alcohol or drug abuse within the past 6 months. 12.Any current mental condition (psychiatric disorder, senility or dementia), which may affect study compliance or prevent understanding of the aims, investigational procedures or possible consequences of the study. 13.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. 14.Anticipated inability to comply with any study procedures, including participation in study visits according to the visit schedule through 24 weeks. 15.Any other reason the investigator deems the subject to be unsuitable for the study. French subjects: In France, a subject will be excluded if he/she has participated in any study using an investigational drug during the previous 30 days.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to evaluate the efficacy of oral losmapimod 7.5 mg BID compared to placebo when 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 [SRI-UR]) through 12 weeks of therapy.;Secondary Objective: The principal secondary objective is to evaluate the efficacy of losmapimod on the time to first occurrence of adjudicated CV death or MI. Additional secondary objectives are included in the protocol page 21.;Primary end point(s): The primary efficacy endpoint is the composite measure of adjudicated MACE that includes the time to first occurrence of CV death, MI, or SRI-UR. If the effect of losmapimod on MACE shows a statistically significant benefit compared to placebo, then the analysis will proceed to testing the hypothesis for the principal secondary endpoint using a serial gate keeping procedure to account for multiplicity. ;Timepoint(s) of evaluation of this end point: the principal analysis will be through 12 weeks, with additional analyses through 4 and 24 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •The principal secondary endpoint is the time to first occurrence of the composite of adjudicated CV death or MI. Additional Secondary Endpoints: •The composite of CV death, MI, or hospitalization for HF. •The expanded composite of arterial CV events, defined as CV death, MI, SRI-UR, or stroke. •The composite of coronary events (defined as CHD death, MI, SRI-UR, or any unplanned coronary artery revascularization). Planned coronary artery revascularizations are those initial or staged interventions performed based on the initial qualifying ACS. •The composite of CV death or hospitalization for HF •The composite of CV death, MI or stroke. •The composite of CV death, MI, SRI-UR, stroke or hospitalisation for HF •The primary and principal secondary endpoints will be evaluated replacing CV death separately with CHD death (“Coronary MACE”) and all-cause death. •The primary and principal secondary endpoints will be evaluated replacing all MI with Type 1 (spontaneous) MI. •Individual components of the composite endpoints (including all-cause mortality). •Definite or probable stent thrombosis. •Any re-hospitalization within 30 days of discharge. ;Timepoint(s) of evaluation of this end point: the principal analysis will be through 12 weeks, with additional analyses through 4 and 24 weeks unless otherwise stated in the endpoint | — |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Korea, Democratic People's Republic of, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Romania, Russian Federation, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Ukraine, United Kingdom, United States
Contacts
Public ContactClincial Trials Helpdesk
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed