Clinical Comparison of Low-dose Rosuvastatin Plus Ezetimibe Combination Therapy and High-dose Rosuvastatin Monotherapy in Patients With Minimal to Intermediate Coronary Artery Disease Without Percutaneous Coronary Intervention

Study Overview
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Brief Summary
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[Purpose of the Clinical Study]:The purpose of this study is to conduct a clinical comparison of low-dose rosuvastatin plus ezetimibe combination therapy and high-dose rosuvastatin monotherapy in patients with minimal to intermediate coronary artery disease without percutaneous coronary intervention to confirm non-inferiority in the reduction of key cardiovascular events. [Hypothesis]:In patients who have not undergone percutaneous coronary intervention for minimal to moderate coronary artery disease, low-dose rosuvastatin and ezetimibe combination therapy are non-inferior in terms of reducing major cardiovascular events compared to high-dose rosuvastatin monotherapy.

Detailed Description
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[Background]:While high-dose statin is becoming more important, there are factors that limit more widespread use of such a treatment due to the possibility of adverse events, especially among the patients from East Asia. These factors include muscle-related diseases, higher liver figures, and onset of diabetes. Meanwhile, the combination treatment of low-dose statin and ezetimibe, which slows down the absorption of LDL cholesterol, can see an equivalent level of LDL cholesterol reduction compared to high-dose statin treatments, while having an advantage in terms of the level of decrease in adverse events. However, further verification is still needed whether the statin + ezetimibe combination therapy and the high-dose statin monotherapy of the same reduction effect against LDL cholesterol would have the same level of clinical utility. Especially with regard to the treatment of patients with minimal to minor coronary artery diseases, there are no available guidelines for the use of statin. In the case of a stenosis lesion with a 50 to 70% severity level, the likelihood of choosing medication over percutaneous coronary artery interventions through a physiological evaluation is increasing compared to the past. Also, some studies suggested that the MACE of an intermediate lesion showed a difference depending on the administration of statin, while percutaneous coronary intervention did not. Therefore, verification of the clinical utility on the said lesions is also necessary. [Clinical Research Plan]: A prospective, multicenter, randomized, and public label clinical study involving a total of 6,356 patients, 3,178 patients each with ezetimibe 10mg/rosuvastatin 5mg (experimental group) and rosuvastatin 20mg (active control group), in patients who have not undergone percutaneous coronary intervention for minimal to moderate coronary artery disease. After random assignment, take the assigned drugs for 3 years and follow-up observation is conducted at 6weeks, 6, 12, and 36 months. Test personnel can follow up through hospital visits or phone visits. The primary end-points are a combined assessment variable of all cause death, cardiovascular deaths, myocardial infarction without death, stroke without death, hospitalization due to unstable angina, and revascularization after random assignment at 36 months.

Official Title
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Clinical Comparison of Low-dose Rosuvastatin Plus Ezetimibe Combination Therapy and High-dose Rosuvastatin Monotherapy in Patients With Minimal to Intermediate Coronary Artery Disease Without Percutaneous Coronary Intervention : A Prospective, Multicenter, Randomized, Open-label Trial

Conditions
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Coronary Artery Disease, Dyslipidemias, Primary Prevention

Intervention / Treatment
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* Drug: Combination drug group of Ezetimibe 10 mg/Rosuvastatin 5 mg
* Drug: Mono drug group of Rosuvastatin 20 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adjusts (19 or older) Patients with suspected stable angina pectoris without coronary artery interventions, who showed a minimal to intermediate coronary artery diseases (a stenosis of 10 to 70% diameter as per QCA) in at least one natural coronary artery in coronary artery angiography or coronary artery CT. Patients who gave their informed consent themselves in writing. Patients who were treated with statin or lipid-lowering agents may participate in the study by changing the existing medicines. Exclusion Criteria: Patients with an intermediate (>30%) lesion on the left main coronary artery. Patients diagnosed with acute coronary artery diseases (STEMI, NSTEMI, Unstable angina) Patients who received percutaneous coronary intervention Patients who have been diagnosed with stroke, transitory ischemic attack, and peripheral artery diseases. Patients diagnosed with variant angina Patients with severe liver diseases or lung diseases and/or malignant tumor Patients with severe valvular heart disease Patients who are hypersensitive or prohibited from using the active substance (Ezetimibe or Rosuvastatin) of the study medicines Patients whose remaining life expectancy is less than a year Patients with cardiogenic shock Pregnant women or women who are planning to get pregnant Patients who are receiving hemodialysis or peritoneal dialysis or received renal transplantation due to end-stage renal failure Patients who participated in other clinical studies within the past three months (except for non-interventional observation studies)

Ages Eligible for Study
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Minimum Age: 19 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination drug group of Ezetimibe 10 mg/Rosuvastatin 5 mg<br>Ezetimibe 10 mg/Rosuvastatin 5 mg, Oral administration once a day, taking it for 3 years | Drug: Combination drug group of Ezetimibe 10 mg/Rosuvastatin 5 mg<br>* Oral administration once a day, taking it for 3 years<br>|
| Active Comparator: Mono drug group of Rosuvastatin 20 mg<br>Rosuvastatin 20 mg , Oral administration once a day, taking it for 3 years | Drug: Mono drug group of Rosuvastatin 20 mg<br>* Oral administration once a day, taking it for 3 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence rates of the compound variables | The occurrence rates of the compound variables of all cause deaths, cardiac deaths, non-fatal myocardial infarction, non-fatal stroke, hospitalization due to unstable angina, and revascularization after taking the study medicine at the time of Visit 5 (36 month) were compared between groups | Visit 5 (36month) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compound end-point | Compound end-points of all cause deaths, cardiac deaths, non-fatal myocardial infarction, non-fatal stroke, hospitalization due to unstable angina, and revascularization after randomization All cause deaths Cardiac deaths Non-fatal myocardial infarction Non-fatal stroke Hospitalization due to unstable angina Revascularization after randomization The satisfaction rate of low-density cholesterol target at visit 6 weeks, 12th month. (Patients with intermediate coronary artery diseases and 50% or higher stenosis: LDL-C less than 70mg/dL, Patients with less than 50% stenosis, intermediate coronary artery diseases, or diabetes: The LDL-C level is less than the target, which is 100mg/dL.) The frequency of myopathy related to statin at visit 6 weeks, 12th month Drop-out rate of the test drug during the study period | Visit 4 (12 month) | 
| The rate of satisfying the target | The rate of satisfying the target for low-density cholesterol at Month 36. (Patients with intermediate coronary artery diseases and 50% or higher stenosis: LDL-C less than 70mg/dL, Patients with less than 50% stenosis, intermediate coronary artery diseases, or diabetes: The LDL-C level is less than the target, which is 100mg/dL.) The occurrence rate of myopathy related to statin at Month 36. Drop-out rate of the test drug during the study period Because the outcome parameters measured in our study have a consensus on their definitions, there is no possibility of potentially different Units of Measure. Additionally, LDL already clearly presents the units, so there is no need for separate Outcome Measures. | Visit 5 (36month) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Disease, Dyslipidemias, Primary Prevention