Effect of Probucol and/or Cilostazol on Mean IMT in Patients With Coronary Heart dIsease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the additional effect of probucol or concomitant administration of cilostazol and probucol on mean carotid artery intima-media thickness (mean IMT) at year 1, 2, and 3.

Detailed Description
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Hyperlipidemic patients who are currently receiving HMGCoA reductase inhibitors(Statins) will be randomized Group A(Control), Group B(Probucol only added group) or Group C(Probucol and cilostazol added group) . Randomization will be done by the minimization method, controlling for the following factors: Country(Korea vs China) and max IMT (≥2.0mm vs.<2.0mm). Group A : HMGCoA reductase inhibitor continued Group B : HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID Group C : HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID +Cilostazol 100 mg PO, BID

Official Title
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Investigate Effect on Mean IMT of Probucol And/or CilosTazol in Patients With Coronary Heart dIsease Taking HMGCoA Reductase Inhibitor Therapy: A Randomized, Multicenter, Multinational Study

Conditions
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Hyperlipidemias

Intervention / Treatment
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* Drug: HMG-CoA Reductase Inhibitor
* Drug: Probucol
* Drug: Cilostazol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) Subjects who are at least 20 y of age at the time of informed consent (male or female) 2) Subjects with coronary heart disease longer than 3 months. 3) Subjects being treated with HMGCoA reductase inhibitors(Statins) 4) Subjects with an max IMT equal to or greater than 1.2 mm 5) Subjects with an LDL-Cholesterol less than 200mg/dl 6) Subjects whose voluntary written informed consent is obtained for participation in this study Exclusion Criteria: 1) Subjects who took probucol within 6 months before participation of the study 2) Subjects who took cilostazol within 3 months before participation of the study 3) Subjects with a history of hypersensitivity to probucol or cilostazol 4) Subjects with homozygous familial hyperlipidemia* 5) Subjects with a triglyceride ( TG) level greater than 400mg/dL at screening 6) Subjects with uncontrolled diabetes : HbA1c level greater than 9% 7) Subjects with New York Heart Association (NYHA) classification: Class Ⅲ and Ⅳ 8) Subjects with a QTc interval greater than 450msec(male) 470msec(female) 9) Subjects with serious ventricular arrythmias (frequent episodes of multifocal ventricular extrasystole) 10) Subjects with atrial fibrillation (including paroxysmal AF) 11) Subjects with unstable angina 12) Subjects with liver and kidney functions that satisfy the following criteria - AST or ALT >100 IU/L, serum creatinine >1.5 mg/dL 13) Subjects who are participating in another clinical trial 14) Subjects with pregnant or possibly pregnant without appropriate contraception control. Appropriate contraception control means that Oral contraception for greater than 4 weeks, surgical contraception including loop insertion, condom use etc. Women who has no possibility of pregnancy because of surgery or menopause should not be regarded the subject with possibly pregnant 15) Subjects with clinically significant disorders of blood coagulation 16) Subjects who are not considered by the physicians to be appropriate to participate in this trial for any other reason

Ages Eligible for Study
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Minimum Age: 20 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group A<br>HMGCoA reductase inhibitor continued | Drug: HMG-CoA Reductase Inhibitor<br>* During the study period, HMGCoA reductase inhibitor is continuously administered to the patients. Dosage regimen: following the package insert of each HMGCoA reductase inhibitor<br>|
| Active Comparator: Group B<br>HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID | Drug: Probucol<br>* In addition to the continued HMGCoA reductase inhibitor treatment, probucol is administered. Dosage regimen: probucol 250-mg tablet, oral administration twice daily with meal(breakfast and dinner)<br>* Other names: HMG-CoA Reductase Inhibitor;|
| Active Comparator: Group C<br>HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID + Cilostazol 100 mg PO, BID | Drug: Cilostazol<br>* In addition to the continued HMGCoA reductase inhibitor treatment, probucol and cilostazol are administered. Dosage regimen: probucol 250-mg tablet, oral administration twice daily with meal(breakfast and dinner) Cilostazol 100-mg tablet, twice daily by the oral route<br>* Other names: HMG-CoA Reductase Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of Carotid artery IMT (mean IMT) between screening and treatment completion(3 years after) or discontinuation | For primary endpoint of Carotid artery IMT, t-test will be conducted for the mean IMT and variation by treatment arm(Group A vs B, Group A vs C). The 2-sided significance level is 5%. Morever, Mantel - Haenszel method can be accepted considering stratification factor or Sub-analysis can be done by each stratum in case of categorical variables. | Baseline(screening), 3years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from enrollment date to the onset of composite cerebrovascular events | Cardiovascular death Myocardial infarction Cerebral infarction Unstable angina and cardiac failure, required hospitalization Coronary revascularization, required hospitalization PCI and coronary artery bypass grafting [CABG] Kaplan-Meier method will be conducted for the time from enrollment date to the onset of composite cerebrovascular and cardiovascular events by treatment arm(Group A vs B, Group A vs C). Overall survival curves and progression-free survival curves are estimated per treatment arm. | enrollment date, onset date(during study period, 3years) | 
| Number of composite cerebrovascular and cardiovascular events(including intervention) | Cardiovascular death Myocardial infarction Cerebral infarction Unstable angina and cardiac failure, required hospitalization Coronary revascularization, required hospitalization PCI and coronary artery bypass grafting [CABG] For the number of composite cerebrovascular and cardiovascular events (including intervention) t-test will be done by treatment arm(Group A vs B, Group A vs C). | enrollment date, onset date(during study period, 3years) | 
| The change of Biomarkers(1) | Metabolic index: Lipid profile (TC, LDL-C, HDL-C, TG) | enrollment date ,onset date(during study period, 3years) | 
| The change of Biomarkers(2) | Inflammatory index: High sensitive C-reactive protein (hsCRP) | enrollment date ,onset date(during study period, 3years) | 
| The change of Biomarkers(3) | Oxidation index:oxidized LDL The change of biomarkers, t-test will be done by treatment arm(Group A vs B, Group A vs C). | enrollment date ,onset date(during study period, 3years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperlipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Probucol, Cilostazol