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

Phase 4

Completed

• Conditions: Hyperlipidemias
• Interventions: Drug: HMG-CoA Reductase Inhibitor; Drug: Probucol; Drug: Cilostazol

• Registration Number: NCT01291641
• Lead Sponsor: Seoul National University Hospital

Brief Summary

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

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

Study Timeline

• Study First Submitted: 2011-01-31
• Study First Submitted QC: 2011-02-06
• Study First Posted: 2011-02-08
• Study Start: 2011-03
• Primary Completion: 2016-12
• Study Completion: 2017-03
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-18
• Last Update Posted: 2019-09-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 342

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A	HMG-CoA Reductase Inhibitor	HMGCoA reductase inhibitor continued
Group B	Probucol	HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID
Group C	Cilostazol	HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID + Cilostazol 100 mg PO, BID

Primary Outcome Measures

Name	Time	Method
Difference of Carotid artery IMT (mean IMT) between screening and treatment completion(3 years after) or discontinuation	Baseline(screening), 3years	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.

Secondary Outcome Measures

Name	Time	Method
The change of Biomarkers(2)	enrollment date ,onset date(during study period, 3years)	Inflammatory index: High sensitive C-reactive protein (hsCRP)
Time from enrollment date to the onset of composite cerebrovascular events	enrollment date, onset date(during study period, 3years)	1. Cardiovascular death; 2. Myocardial infarction; 3. Cerebral infarction; 4. Unstable angina and cardiac failure, required hospitalization; 5. Coronary revascularization, required hospitalization; 6. 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.
Number of composite cerebrovascular and cardiovascular events(including intervention)	enrollment date, onset date(during study period, 3years)	1. Cardiovascular death; 2. Myocardial infarction; 3. Cerebral infarction; 4. Unstable angina and cardiac failure, required hospitalization; 5. Coronary revascularization, required hospitalization; 6. 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).
The change of Biomarkers(1)	enrollment date ,onset date(during study period, 3years)	Metabolic index: Lipid profile (TC, LDL-C, HDL-C, TG)
The change of Biomarkers(3)	enrollment date ,onset date(during study period, 3years)	Oxidation index:oxidized LDL; The change of biomarkers, t-test will be done by treatment arm(Group A vs B, Group A vs C).

Trial Locations

Locations (5)

Dong-A Medical Center; 🇰🇷 Seogu, Busan, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Boramae Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Gangnam-Gu, Korea, Republic of

Seoul National University Bundang Hospital; 🇰🇷 Seongnam-si, Gyeonggi-do, Korea, Republic of