IMPROVE-IT

PI: Dr. Kul Aggarwal
Coordinator: Alisa Lau-Sieckman

The purpose of this study is to compare two drugs, ezetimibe/simvastatin combination and simvastatin alone in patients who have had a recent heart attack or unstable chest pain. Patients will be followed to see if there is a difference in future cardiac events depending on which drug they are randomized to.

Inclusion:

1. Subject may be of either sex and of any race.
2. Subject must have NSTE-ACS or STEMI according to the following criteria
   1. Clinically stable NSTE-ACS pts who meet all of the following criteria will be eligible to enter within 10 days of acute admittance into a hospital.
      1. The subject has experienced symptoms of cardiac ischemia at rest with at least one episode lasting at least 10 minutes within 24 hours of the clinical event prompting hospitalization.
      2. At least 50 years of age
      3. Meet any 1 of the following criteria:
         1. Electrocardiogram changes in at least two contiguous leads characterized by either of the following:
         • New or presumably new ST-segment depression > or = 0.1 mV or
         • Transient (<30 minutes) ST-segment elevation > or = 0.1 mV.
         2. Any of the following biomarkers elevated above the upper limit of normal (ULN):
         • Troponin I
         • Creatine kinase-MB fraction (CK-MB)
         3. Diabetes mellitus
         4. History of prior MI
         5. History of peripheral arterial disease
         6. History of cerebrovascular disease
         7. History of CABG > or = 3 years prior to entry
         8. Multivessel coronary artery disease previously documented by catheterization (2 or 3 vessels with >50% stenosis)
   2. Clinically stable high risk STEMI pts who meet the following criteria may be enrolled within 10 days of acute admittance into a hospital:
      1. The subject has experienced symptoms of cardiac ischemia at rest with at least one episode lasting at least 30 minutes in conjunction with the clinical event prompting hospitalization; and
      2. The subject must have all three of the following:
         1. New or presumably new electrocardiogram (ECG) changes in at least two contiguous leads characterized by any of the following:
         • Persistent ST-segment elevation > or = 0.1 mV
         • Q waves
         • Left bundle branch block (LBBB)
         2. Any of the following biomarkers elevated above the ULN:
         • Troponin I
         • CK-MB
         3. One of the following characteristics:
            • Presence of an anterior infarction
            • 50 years of age or older
3. Subject must meet the following criteria for LDL-C concentrations at the time of admittance into a hospital:
   1. A statin-naive subject will be eligible to enroll if his/her LDL-C concentration is 50-125 mg/dl.
   2. A subject receiving chronic statin therapy will be eligible to enroll if his/her LDL-C is 50-100 mg/dl.
4. Subject must have a fasting plasma triglyceride (TG) level < 350 mg/dl.
5. Subject’s clinical laboratory tests must be within reference ranges or clinically acceptable to the investigator/sponsor.
   
6. At Screening/Randomization each woman of childbearing potential must agree to use a medically accepted method of contraception while receiving protocol-specified medication and for 6 weeks after stopping the medication. All postmenarchal women who are < 2 years menopausal or who have not had surgical sterilization or a hysterectomy are considered to be women of childbearing potential. Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), oral or injectable hormonal contraceptive, and surgical sterilization (e.g., hysterectomy or tubal ligation).
   
7. Each women of child-bearing potential who is not currently sexually active must agree to use a medically accepted method of contraception should she become sexually active while participating in the study.
   

Exclusion:

1. Subject who is clinically unstable.  A subject is considered clinically unstable if he/she displays any of the following spontaneous events for 24 hours prior to Screening/Randomization:
   1. Hemodynamic events:
      1. Hypotension
      2. Pulmonary edema/CHF
      3. Acute mitral regurgitation
      4. Acute ventricular septal defect
   2. Ischemic events:
      1. Stroke
      2. Recurrent symptoms of cardiac ischemia
   3. Arrhythmic events:
      1. Ventricular fibrillation
      2. Sustained ventricular tachycardia
      3. Complete heart block
      4. High grade second degree heart block
2. Subject who must continue to receive treatment that is listed in Table 2.

   Table 2 Prohibited Medications for Entry into the Study: Medications That Must Be Stopped at Entry Protocol No. P04103

   Prohibited Medications
   Probucol
   Amiodarone
   Cyclosporine
   Fibric Acid derivatives (fibrates)
   Resins
   Niacin, >100 mg/day
   Danazol
   Antifungal azoles (itraconazole, fluconazole, and ketoconazole)a
   Macrolide/Ketolide antibiotics (eg, clarithromycin, erythromycin, telithromycin)a
   Protease inhibitors
   Nefazodone
   Any investigational drugs
   Diltiazem
   Verapamil (sustained release formulations)
   Verapamil
   Grapefruit juice >1 quart/day

   a: Short-term therapy of antifungal or antibiotics is acceptable, provided study
   medication is interrupted during the administration and restarted after shortterm
   therapy is completed.

    
3. The investigator feels that discontinuation of existing lipid-lowering regimen poses a risk to the subject.
4. The subject is receiving statin therapy with LDL-C lowering potency greater than simvastatin 40 mg (e.g., atorvastatin 40-80 mg, all doses of rosuvastatin, and all doses of ezetimibe/simvastatin combination.
5. Subject has an allergy/sensitivity to any statin, ezetimibe, and/or their excipients.
6. Subject has active liver disease or persistent unexplained serum transaminase elevations (> or = 2 x ULN).
7. Subject has a history of alcohol and/or drug abuse.
8. Subject is a pregnant or lactating woman, or woman intending to become pregnant.
9. Subject with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the vestigator, would interfere with the study evaluations or optimal participation in the study.
10. Subject who has used any investigational drugs within 30 days of Screening/Randomization.
11. Subject who is participating in any other clinical study involving any investigational drug or device, other than the EARLY-ACS Study (Protocol No. P03684).
12. Subject with prior enrollment in the current study (Protocol No. P04103).
13. Subject who is part of the staff personnel directly involved with this study.
14. Subject who is a family member of the investigational study staff.

Action:

1. Determine if patient fits major study criteria.
2. Determine if patient is interested in joining a clinical trial.
3. Call Alisa Lau-Sieckman (beeper 443-9259) and/or on-call research nurse (on-call beeper 499-8084) or Dr. Aggarwal to complete screening of patient.

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Last Revised: 06/28/2006