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Cardiovascular Medicine - Active Clinical Trials
SOLID-TIMI 52


Primary Investigator: Kul Aggarwal, MD      

Study Coordinator: Jane Spencer, RN

Status: Active - open to enrollment             

Study Title: A Clinical Outcomes Study of Darapladib versus Placebo in Subjects Following Acute Coronary Syndrome (ACS) to Compare the Incident of Major Adverse Cardiovascular Events

Purpose: The primary objective of this study is to evaluate clinical efficacy of long-term treatment with Darapladib Enteric Coated Tablets, 160 mg (oral once daily dose) as compared to a placebo when added to standard of care in an ACS patient population on the incidence of first occurrence of the composite of major adverse cardiovascular events; i.e., cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke.

Inclusion Criteria:
1. Hospitalization for ACS (unstable angina, non-ST segment elevation MI, or ST segment elevation MI) 30 days prior to randomization:
     
a. Unstable angina (UA) is defined as ischemic chest discomfort (or equivalent) that occurs at rest with at least one episode lasting ≥10 minutes and is accompanied by new or presumably new ST segment deviation (transient [<20 minutes] elevation ≥0.1mV or dynamic horizontal/down-sloping depression ≥0.05mV) in at least two contiguous leads without diagnostic biochemical changes in cardiac enzymes (serum troponin I or T, or creatine kinase-MB).
     
b. Non-ST segment elevation MI (NSTEMI) is defined as ischemic chest discomfort (or equivalent) that occurs at rest with at least one episode lasting ≥10 minutes and is accompanied by a diagnostic elevation in cardiac biomarkers of myocardial injury (serum troponin I or T, or creatine kinase-MB) above the upper limit of normal without persistent ST segment elevation.
     
c. ST segment elevation MI (STEMI) is defined as prolonged symptoms of ischemic chest discomfort (or equivalent) at rest (with at least one episode lasting >20 minutes) and new or presumably new electrocardiographic changes (persistent ST segment elevation ≥0.1 mV in ≥2 contiguous precordial leads or ≥2 adjacent limb leads or new LBBB) that are accompanied by a diagnostic elevation in cardiac biomarkers (serum troponin I or T, or creatine kinase-MB) above the upper limit of normal.
2.  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 prior to qualifying ACS event.
     
c. Diabetes mellitus requiring pharmacotherapy.
     
d. Significant renal dysfunction (defined as estimated glomerular filtration rate [eGFR] ≥30 and ≤59 mL/min per 1.73 m2).
     
e. Polyvascular disease manifested as coexistent clinically diagnosed arterial disease in at least two arterial territories, defined as:
        
cerebrovascular disease defined as carotid artery disease, or as prior ischemic stroke that occurred >3 months prior to randomization 
           
OR
        
peripheral arterial disease (PAD)
3. The subject must be clinically stable for 24 hours prior to randomization (clinical stability is defined as the absence of chest pain, hemodynamic instability [e.g., hypotension, requirement for inotropic therapy], or significant arrhythmia [e.g., arrhythmia requiring treatment]).
4. For subjects in whom a percutaneous coronary intervention (PCI) is planned as part of management for the qualifying ACS event, the subjects should undergo PCI prior to randomization whenever possible.

Exclusion Criteria:
1.   Clinical or laboratory manifestations of ACS (e.g., chest pain, ECG changes or increase in cardiac enzymes) that is not believed to be thrombotic in origin or is believed to be secondary to other apparent illness (e.g., sepsis, profound anemia, tachycardia, hypertensive emergency or decompensated heart failure).
2.   Absence of obstructive coronary artery disease (i.e., at least one stenosis [>50%] in a major vessel, major branch or bypass graft) based on angiography, if performed, between the time of presentation with ACS and randomization.
3.   Planned coronary artery bypass graft (CABG) surgery or CABG surgery performed following the qualifying event and prior to randomization.
4.   Current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase >1.5 x upper limit of normal [ULN]; or ALT or AST >2.5 x ULN) or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
5.   Severe renal impairment (e.g., patients with an eGFR11 <30 mL/min/1.73 m2 or receiving chronic dialysis) or history of nephrectomy or kidney transplant (regardless of renal function).
6.   Current severe heart failure (New York Heart Association [NYHA] class III or IV).   
7.   Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy.
8.   Any life-threatening condition with life expectancy <2 years, other than vascular disease, that might prevent the subject from completing the study.
9.   Severe asthma that is poorly controlled on pharmacotherapy.
10. Positive pregnancy test (all female subjects of childbearing potential must have urine or serum β-human chorionic gonadotropin [hCG] pregnancy test performed within seven days prior to randomization) or is known to be pregnant or lactating.  
11. History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions or severe allergic responses.
12. Alcohol or drug abuse within the past six months, or 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. Current or planned chronic administration of strong oral or injectable cytochrome P-450 isoenzyme 3A4 (CYP3A4) inhibitors.
Note: Examples of strong CYP3A4 inhibitors include, but are not limited to the antiretrovirals, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir; the macrolide/ketolide antibiotics clarithromycin, telithromycin, troleandomycin; and the oral antifungals ketoconazole, itraconazole. Of note, weaker CYP3A4 inhibitors are allowed, including verapamil, diltiazem, or amiodarone.
14. Subjects with two known birth parents of at least 50% Japanese, Chinese, or Korean ancestry (or if unknown, a reasonable likelihood of such ancestry) must have a blood sample collected for assessment of Lp-PLA2 activity by the central laboratory prior to randomization. Those with Lp-PLA2 activity 10 nmol/min/mL will be excluded from participation in the study.
Note: Subjects homozygous for the V279F variant have no circulating levels of Lp-PLA2 and would not expect to benefit from Lp-PLA2 lowering therapy. This allele is most common in those of Japanese, Chinese and Korean ancestry.
15. Previous exposure to darapladib (SB-480848).
16. Use of another investigational product within 30 days or five half-lives (whichever is the longer) preceding the first dose of darapladib or matching placebo.
17. Currently in a study of an investigational device.
18. Any other reason the investigator deems the subject to be unsuitable for the study.

Actions:
1.    Determine if patient fits major study criteria
2.    Determine if patient is interested in joining a clinical trial.
3.    Call Jane Spencer (beeper: 573-397-0554) and/or on-call research nurse (on-call beeper 573-499-8084) or Dr. Aggarwal to complete screening of subject.




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