IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (P04103)

Completed

Phase 3 Results

Trial Description

This is a randomized, active-control, double-blind study of subjects with stabilized high-risk acute coronary syndrome (ACS). The primary objective is to evaluate the clinical benefit of Ezetimibe/Simvastatin Combination 10/40 (single tablet, under the brand VYTORIN in the United States) compared with Simvastatin 40 mg. As per the original protocol, if low-density lipoprotein cholesterol (LDL-C) response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped). Clinical benefit will be defined as the reduction in the risk of the occurrence of the composite endpoint of cardiovascular (CV) death, major coronary events, and stroke.

Conditions

Interventions

  • Simvastatin Drug
    Intervention Desc: Simvastatin 40 mg per day from randomization through the end of participation. As per the original protocol, if LDL-C response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped).
    ARM 1: Kind: Experimental
    Label: simvastatin
  • Ezetimibe (Zetia)Drug
    Intervention Desc: Ezetimibe (pronounced /ɛˈzɛtəmɪb/) is an anti-hyperlipidemic medication which is used to lower cholesterol levels. It acts by decreasing cholesterol absorption in the intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with statins (e.g. ezetimibe/simvastatin, marketed as Vytorin and Inegy) when cholesterol levels are unable to be controlled on statins alone.
  • Ezetimibe/simvastatin Drug
    Other Names: Vytorin; Inegy
    Intervention Desc: Ezetimibe/simvastatin 10/40 mg per day from randomization through the end of participation. As per the original protocol, if LDL-C response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped).
    ARM 1: Kind: Experimental
    Label: ezetimibe/simvastatin
  • Placebo for simvastatin 40 mg Drug
    Intervention Desc: one or two tablets orally daily
    ARM 1: Kind: Experimental
    Label: ezetimibe/simvastatin
    Description: One Ezetimibe 10 mg/simvastatin 40 mg combination tablet and two simvastatin 40 mg placebo tablets once per day.
    ARM 2: Kind: Experimental
    Label: simvastatin
    Description: One simvastatin 40 mg tablet, one ezetimibe/simvastatin combination 10/40 placebo tablet and one simvastatin 40 mg placebo tablet once per day.
  • Placebo for ezetimibe 10 mg/simvastatin 40 mg combination Drug
    Intervention Desc: one tablet orally daily.
    ARM 1: Kind: Experimental
    Label: simvastatin
    Description: One simvastatin 40 mg tablet, one ezetimibe/simvastatin combination 10/40 placebo tablet and one simvastatin 40 mg placebo tablet once per day.

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Patient Involvement

Patients will be randomized to either ezetimibe/simvastatin 10/40 mg per day from randomization through the end of participation (if LDL-C response is inadequate, the dose of simvastatin may be increased to 80 mg) or simvastatin 40 mg per day from randomization through the end of participation (if LDL-C response is inadequate, the dose of simvastatin may be increased to 80 mg). Patient will also need to be followed with blood tests during study to determine response to drug.

Outcomes

Type Measure Time Frame Safety Issue
Primary To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any cardiovascular events, non-fatal coronary events (such as heart attack), and non-fatal strokes.
Secondary To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any cause, non-fatal coronary events (such as heart attack), and non-fatal stroke; to measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on coronary heart disease-related death, non-fatal heart attack, and by-pass surgery; to measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any cardiovascular events, non-fatal heart attack, angina leading to hospitalization, by-pass surgery, and non-fatal stroke.
Primary To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any cardiovascular events, non-fatal coronary events (such as heart attack), and non-fatal strokes Trial will continue until a minimum of 5,250 subjects have a primary endpoint event and each subject is followed for a minimum of 2.5 years. Thus, the anticipated completion dates below may be adjusted on the basis of actual event occurrance. No
Secondary To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any cause, non-fatal coronary events (such as heart attack), and non-fatal stroke Trial will continue until a minimum of 5,250 subjects have a primary endpoint event and each subject is followed for a minimum of 2.5 years No
Secondary To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on coronary heart disease-related death, non-fatal heart attack, and by-pass surgery Trial will continue until a minimum of 5,250 subjects have a primary endpoint event and each subject is followed for a minimum of 2.5 years No
Secondary To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any cardiovascular events, non-fatal heart attack, angina leading to hospitalization, by-pass surgery, and non-fatal stroke Trial will continue until a minimum of 5,250 subjects have a primary endpoint event and each subject is followed for a minimum of 2.5 years No
Primary Time to First Occurrence of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) Up to approximately 9 years No
Secondary Time to First Occurrence of Death From Any Cause, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) Up to approximately 9 years No
Secondary Time to First Occurrence of Coronary Heart Disease (CHD) Death, Non-fatal MI, or Urgent Coronary Revascularization With PCI or CABG ≥ 30 Days After Randomization (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) Up to approximately 9 years No
Secondary Time to First Occurrence of CV Death, Nonfatal MI, UA With Hospitalization, All Revascularization Occurring ≥30 Days After Randomization, and Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event) Up to approximately 9 years No

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