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

Hyperlipidemias Clinical Trial

— IMPACTonIMT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01291641
• Other study ID #: IMT-01
• Status: Completed
• Phase: Phase 4
• Start date: March 2011
• Est. completion date: March 2017

Study information

• Verified date: September 2019
• Source: Seoul National University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 342
• Est. completion date: March 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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 ? and ?

• 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

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Heart Diseases
• Hyperlipidemias
• Hyperlipoproteinemias
• Myocardial Ischemia

Intervention

Drug:
• HMG-CoA Reductase Inhibitor
During the study period, HMGCoA reductase inhibitor is continuously administered to the patients. Dosage regimen: following the package insert of each HMGCoA reductase inhibitor
• Probucol
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)
• Cilostazol
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

Locations

Country	Name	City	State
Korea, Republic of	Dong-A Medical Center	Seogu	Busan
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Boramae Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul	Gangnam-Gu
Korea, Republic of	Seoul National University Hospital	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Seoul National University Hospital	Korea Otsuka Pharmaceutical Co., Ltd.

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (25)

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Matsuzawa Y, Yamashita S, Funahashi T, Yamamoto A, Tarui S. Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyperHDL2 cholesterolemia with abnormal cholesteryl ester transfer. Am J Cardiol. 1988 Jul 25; — View Citation

Park SY, Lee JH, Shin HK, Kim CD, Lee WS, Rhim BY, Shin YW, Hong KW. Synergistic efficacy of concurrent treatment with cilostazol and probucol on the suppression of reactive oxygen species and inflammatory markers in cultured human coronary artery endothe — View Citation

Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, Cuddy TE, Moyé LA, Piller LB, Rutherford J, Simpson LM, Braunwald E. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) — View Citation

Rinninger F, Wang N, Ramakrishnan R, Jiang XC, Tall AR. Probucol enhances selective uptake of HDL-associated cholesteryl esters in vitro by a scavenger receptor B-I-dependent mechanism. Arterioscler Thromb Vasc Biol. 1999 May;19(5):1325-32. — View Citation

Sawayama Y, Shimizu C, Maeda N, Tatsukawa M, Kinukawa N, Koyanagi S, Kashiwagi S, Hayashi J. Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST). J — View Citation

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Tardif JC, Cöté G, Lespérance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, de Guise P. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med. 1997 Aug 7;337 — View Citation

Tawara K, Tomikawa M, Abiko Y. Mode of action of probucol in reducing serum cholesterol in mice. Jpn J Pharmacol. 1986 Jan;40(1):123-33. — View Citation

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Tomikawa M, Nakayasu T, Tawara K, Abiko Y. Effect of probucol on serum lipoprotein levels in normal and dyslipoproteinemic mice. Atherosclerosis. 1981 Oct;40(2):101-13. — View Citation

Yamashita S, Hbujo H, Arai H, Harada-Shiba M, Matsui S, Fukushima M, Saito Y, Kita T, Matsuzawa Y. Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. — View Citation

Yoshikawa T, Mitani K, Kotosai K, Nozako M, Miyakoda G, Yabuuchi Y. Antiatherogenic effects of cilostazol and probucol alone, and in combination in low density lipoprotein receptor-deficient mice fed with a high fat diet. Horm Metab Res. 2008 Jul;40(7):47 — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	The change of Biomarkers(1)	Metabolic index: Lipid profile (TC, LDL-C, HDL-C, TG)	enrollment date ,onset date(during study period, 3years)
Secondary	The change of Biomarkers(2)	Inflammatory index: High sensitive C-reactive protein (hsCRP)	enrollment date ,onset date(during study period, 3years)
Secondary	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)