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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00202878
First received: September 13, 2005
Last updated: November 2, 2015
Last verified: November 2015
  Purpose
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.

Condition Intervention Phase
Hypercholesterolemia
Myocardial Infarction
Drug: ezetimibe/simvastatin
Drug: simvastatin
Drug: Placebo for simvastatin 40 mg
Drug: Placebo for ezetimibe 10 mg/simvastatin 40 mg combination
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial - IMPROVE IT)

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • 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) [ Time Frame: Up to approximately 9 years ] [ Designated as safety issue: No ]
    The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: cardiovascular death, major coronary Event (non-fatal myocardial infarction [MI], documented unstable angina [UA] requiring hospitalization, or coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) ≥ 30 days after randomization), or non-fatal Stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced cardiovascular death, major coronary event, or non-fatal stroke within 7 years from randomization.


Secondary Outcome Measures:
  • 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) [ Time Frame: Up to approximately 9 years ] [ Designated as safety issue: No ]
    The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: death from any cause, major coronary event (non-fatal myocardial infarction, documented unstable angina requiring hospitalization, or coronary revascularization with percutaneous coronary intervention or coronary artery bypass grafting ≥ 30 days after randomization), or non-fatal stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced death from any cause, major coronary event, or non-fatal stroke within 7 years from randomization.

  • 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) [ Time Frame: Up to approximately 9 years ] [ Designated as safety issue: No ]
    The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: CHD death, non-fatal MI, or urgent coronary revascularization with PCI or CABG ≥ 30 days after randomization. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced CHD death, non-fatal MI, or urgent coronary revascularization with PCI or CABG ≥ 30 days after randomization within 7 years from randomization.

  • 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) [ Time Frame: Up to approximately 9 years ] [ Designated as safety issue: No ]
    The time (in months) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, non-fatal MI, documented UA that requires admission into a hospital, all revascularization (including non-coronary) occurring at least 30 days after randomization, and non-fatal stroke. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced CV death, non-fatal MI, unstable angina with hospitalization, all revascularization occurring ≥ 30 days after randomization, and non-fatal stroke within 7 Years from randomization.


Enrollment: 18144
Study Start Date: October 2005
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ezetimibe/simvastatin
One Ezetimibe 10 mg/simvastatin 40 mg combination tablet and two simvastatin 40 mg placebo tablets once per day.
Drug: ezetimibe/simvastatin
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).
Other Names:
  • Vytorin
  • Inegy
Drug: Placebo for simvastatin 40 mg
one or two tablets orally daily
Active Comparator: simvastatin
One simvastatin 40 mg tablet, one ezetimibe/simvastatin combination 10/40 placebo tablet and one simvastatin 40 mg placebo tablet once per day.
Drug: simvastatin
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).
Other Name: Zocor
Drug: Placebo for simvastatin 40 mg
one or two tablets orally daily
Drug: Placebo for ezetimibe 10 mg/simvastatin 40 mg combination
one tablet orally daily.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinically stable participants may be eligible to enroll within 10 days following hospital admission with high-risk acute coronary syndrome (either ST-elevation myocardial infarction [STEMI] or Non-STEMI or unstable angina)
  • Participants not taking a statin must have an LDL-C of 125 mg/dl or less. Participants taking a statin must have an LDL-C of 100 mg/dl or less.

Exclusion Criteria:

  • Pregnant or lactating woman, or intending to become pregnant
  • Participant with active liver disease or persistent unexplained serum transaminase elevation
  • History of alcohol or drug abuse
  • History of sensitivity to statin or ezetimibe
  • A participant for whom discontinuation of existing lipid lowering regimen poses an unacceptable risk.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00202878

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00202878     History of Changes
Other Study ID Numbers: P04103  MK-0653A-080 
Study First Received: September 13, 2005
Results First Received: August 28, 2015
Last Updated: November 2, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Merck Sharp & Dohme Corp.:
hypercholesterolemia
myocardial infarction
cholesterol
randomized controlled trials
acute coronary syndrome
angina

Additional relevant MeSH terms:
Syndrome
Infarction
Myocardial Infarction
Acute Coronary Syndrome
Hypercholesterolemia
Disease
Pathologic Processes
Ischemia
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Simvastatin
Ezetimibe, Simvastatin Drug Combination
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 27, 2016