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

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).

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.

Eligibility Criteria:
Inclusion Criteria:

1. Men and women ≥40 years of age
2. Written informed consent from the subject
3. 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
4. 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
5. 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
6. Revascularization, if required or planned, must occur prior to randomization

Exclusion Criteria:

1. Subjects enrolled in another experimental (interventional)protocol within the past 30 days prior to Screening.
2. 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)
3. 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)
4. Active cholecystitis, gall bladder symptoms, or any hepatobiliary abnormalities
5. The presence of severe renal impairment (creatinine clearance \[CrCl\] \<30 mL/min or creatinine \>3 x ULN),nephrotic syndrome, or subjects undergoing dialysis
6. Uncontrolled diabetes mellitus (known hemoglobin A1c \[HbA1c\] \>11% within the last 1 month prior to Screening)
7. 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).
8. Subjects who have a history of alcohol or drug abuse within 1 year of study entry
9. Subjects living too far from participating center or unable to return for follow-up visits
10. 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
11. Known human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), or tuberculosis infection
12. Acute bacterial, fungal or viral infection
13. Subjects currently taking drugs that are potent inhibitors of cytochrome P450 unless they can be withdrawn
14. Subjects with New York Heart Association (NYHA) Class III or IV heart failure, or if known, left ventricular ejection fraction (LVEF) \<30
15. Subjects with moderate or severe aortic stenosis, aortic regurgitation, mitral stenosis or mitral regurgitation
16. Ventricular arrhythmias requiring chronic drug treatment or implantable cardioverter-defibrillator (ICD)
17. Subjects with no stenosis or stenosis \<50% on angiography, if known
18. Subjects with a pacemaker or persistent left bundle branch block (LBBB)
19. Fasting triglyceride levels of ≥400 mg/dL (4.5 mmol/L)
20. Subjects who have a history of statin intolerance or a significant myopathy or rhabdomyolysis with any lipid altering drugs
21. 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