VISTA-16 Trial: Evaluation of Safety and Efficacy of Short-term A-002 Treatment in Subjects With Acute Coronary Syndrome

Study Overview
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Brief Summary
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The objective of this study is to evaluate the safety and efficacy of short-term A-002 treatment on morbidity and mortality when added to atorvastatin and standard of care in subjects with an acute coronary syndrome (ACS).

Detailed Description
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A double-blind randomized parallel group placebo controlled study in subjects presenting with an ACS. Up to 6500 subjects will be randomized to receive either A-002 500 mg once daily (QD) or placebo tablets in addition to atorvastatin QD and standard of care. Treatment will be 16 weeks in duration. The dose of atorvastatin shall be adjusted after 8 weeks if subject's LDL-C is ≥100 mg/dL, but otherwise must remain stable throughout the16-week duration of study. The survival status for all enrolled subjects will be ascertained 6 months after they complete the study. Randomization must occur within ≤96 hours of hospitalization for the index ACS event, or if already hospitalized, within ≤96 hours of index event diagnosis. Follow-up visits will occur on Weeks 1, 2, 4, 8, and 16. A 6 month follow-up visit will also occur.

Official Title
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VISTA-16 Trial: Evaluation of the Safety and Efficacy of Short-Term A-002 Treatment in Subjects With Acute Coronary Syndromes

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: A-002, varespladib methyl
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥40 years of age Written informed consent from the subject A diagnosis of unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI) Unstable angina is defined as: Chest pain symptomatic of ischemia or angina occurring at rest or on minimal exertion with a pattern of increasing frequency or severity, lasting >10 minutes and consistent with myocardial ischemia within 24 hours prior to hospitalization and New or dynamic ST-segment depression or prominent T-wave inversion changes in at least 2 contiguous leads and In addition subjects meeting the above criteria for unstable angina must also have either troponin I, troponin T or CKMB above the LLD but below the 99th percentile of the upper reference limit (URL) and not due to cardioversion or underlying cardiovascular (CHF, cardiomyopathy) or renal disease NSTEMI is defined as: Chest pain symptomatic of ischemia No electrocardiogram (ECG) changes, or ST-depression, or T wave changes(i.e., no new Q waves on serial ECGs)and Increase in cardiac troponin > local limit for the definition of myocardial infarction or increase in CK-MB isoenzyme > URL STEMI is defined as: Chest pain symptomatic of ischemia ST segment elevation and associated T wave changes or ST-segment elevation of at least 2 mm in 2 contiguous leads, either of which persisting for longer than 15 minutes and Increase in cardiac troponin > local limit for the definition of myocardial infarction or increase in CK-MB >URL All subjects must have the presence of at least one of the following risk factors: Diabetes Mellitus or Presence of any 3 of the following characteristics of metabolic syndrome Waist circumference >102 cm in males, >88 cm in females Serum triglycerides ≥150 mg/dL (≥1.7 mmol/L) HDL-C <40 mg/dL (<1 mmol/L) in males, <50 mg/dL (<1.3 mmol/L) in females Blood pressure ≥130/85 mmHg Plasma glucose ≥110 mg/dL (≥6.1 mmol/L) or history of cerebrovascular disease (stroke or TIA) or history of peripheral vascular disease or previous CABG or previous documented myocardial infarction or previous coronary revascularization Subjects must be randomized within ≤96 hours of hospital admission for the index event, or if already hospitalized, within ≤96 hours of index event diagnosis Revascularization, if required or planned, must occur prior to randomization Exclusion Criteria: Subjects enrolled in another experimental (interventional)protocol within the past 30 days prior to Screening. Subjects treated for cancer within the previous 5 years except for skin basal cell carcinoma or carcinoma in situ of the cervix, with measures other than a minor, complete surgical excision or radiation therapy (e.g. chemotherapy) The presence of any severe liver disease with cirrhosis, active hepatitis, active chronic hepatitis, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x ULN, biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN) Active cholecystitis, gall bladder symptoms, or any hepatobiliary abnormalities The presence of severe renal impairment (creatinine clearance [CrCl] <30 mL/min or creatinine >3 x ULN),nephrotic syndrome, or subjects undergoing dialysis Uncontrolled diabetes mellitus (known hemoglobin A1c [HbA1c] >11% within the last 1 month prior to Screening) Females who are nursing, pregnant, or intend to become pregnant during the time of the study, or females of childbearing potential who have a positive pregnancy test during screening evaluation. Women of child-bearing potential must also use a reliable method of birth control during the study and for 1 month following completion of therapy. A reliable method for this study is defined as one of the following: oral or injectable contraceptives, intrauterine device (IUD), contraceptive implants, tubal ligation, hysterectomy, a double barrier method (diaphragm with spermicidal foam or jelly, or a condom). Subjects who have a history of alcohol or drug abuse within 1 year of study entry Subjects living too far from participating center or unable to return for follow-up visits Subjects who in the opinion of the Investigator are a poor medical or psychiatric risk for therapy with an investigational drug, are unreliable, or have an incomplete understanding of the study which may affect their ability to take drugs as prescribed or comply with instructions Known human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), or tuberculosis infection Acute bacterial, fungal or viral infection Subjects currently taking drugs that are potent inhibitors of cytochrome P450 unless they can be withdrawn Subjects with New York Heart Association (NYHA) Class III or IV heart failure, or if known, left ventricular ejection fraction (LVEF) <30 Subjects with moderate or severe aortic stenosis, aortic regurgitation, mitral stenosis or mitral regurgitation Ventricular arrhythmias requiring chronic drug treatment or implantable cardioverter-defibrillator (ICD) Subjects with no stenosis or stenosis <50% on angiography, if known Subjects with a pacemaker or persistent left bundle branch block (LBBB) Fasting triglyceride levels of ≥400 mg/dL (4.5 mmol/L) Subjects who have a history of statin intolerance or a significant myopathy or rhabdomyolysis with any lipid altering drugs Subjects currently treated with the maximum labeled dose of a statin and not at LDL-C target for their level of risk as defined by NCEP ATP III

Ages Eligible for Study
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Minimum Age: 40 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: A-002 500 mg<br>Once daily oral administration | Drug: A-002, varespladib methyl<br>* A-002 administered once daily in addition to atorvastatin and standard of care<br>|
| Placebo Comparator: Matched Placebo<br>Once daily oral administration | Drug: Placebo<br>* Placebo administered once daily in addition to atorvastatin and standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Objective of the Study | To determine whether 16 weeks of treatment with A-002 plus atorvastatin and standard of care is superior to placebo plus atorvastatin and standard of care for reducing the hazard of the first occurrence of the combined endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or documented unstable angina with objective evidence of ischemia requiring hospitalization. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Objective of the Study | To determine whether A-002 plus atorvastatin and standard of care is superior to placebo plus atorvastatin and standard of care for reducing the occurrence of the hazard of the combined endpoint of all-cause mortality, non-fatal myocardial infarction, non-fatal stroke or documented unstable angina with objective evidence of ischemia requiring hospitalization or multiple occurrences of the non-fatal components of the composite primary endpoint. | 2, 4, 8, 16 weeks and 6 months |