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

NCT01291641 | Completed Phase 4 DMC

• 1 other identifier: IMT-01
• Study Type: interventional
• Target: 342
• Locations: 1 country
• Sites: 5

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.

Conditions

Hyperlipidemias

Keywords

Hyperlipidemias; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Probucol; Cilostazol

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Time from enrollment date to the onset of composite cerebrovascular events

  enrollment date, onset date(during study period, 3years)

• Number of composite cerebrovascular and cardiovascular events(including intervention)

  enrollment date, onset date(during study period, 3years)

• The change of Biomarkers(1)

  enrollment date ,onset date(during study period, 3years)

• The change of Biomarkers(2)

  enrollment date ,onset date(during study period, 3years)

• The change of Biomarkers(3)

  enrollment date ,onset date(during study period, 3years)

Study Arms (3)

Group A

PLACEBO COMPARATOR

HMGCoA reductase inhibitor continued

Drug: HMG-CoA Reductase Inhibitor

Group B

ACTIVE COMPARATOR

HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID

Drug: Probucol

Group C

ACTIVE COMPARATOR

HMGCoA reductase inhibitor continued + Probucol 250 mg PO, BID + Cilostazol 100 mg PO, BID

Drug: Cilostazol

Interventions

HMG-CoA Reductase Inhibitor DRUG

During the study period, HMGCoA reductase inhibitor is continuously administered to the patients. Dosage regimen: following the package insert of each HMGCoA reductase inhibitor

Group A

Probucol DRUG

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)

Also known as: HMG-CoA Reductase Inhibitor

Group B

Cilostazol DRUG

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

Also known as: Probucol, HMG-CoA Reductase Inhibitor

Group C

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \) Subjects who are at least 20 y of age at the time of informed consent (male or female)
• \) Subjects with coronary heart disease longer than 3 months.
• \) Subjects being treated with HMGCoA reductase inhibitors(Statins)
• \) Subjects with an max IMT equal to or greater than 1.2 mm
• \) Subjects with an LDL-Cholesterol less than 200mg/dl
• \) Subjects whose voluntary written informed consent is obtained for participation in this study

You may not qualify if:

• \) Subjects who took probucol within 6 months before participation of the study
• \) Subjects who took cilostazol within 3 months before participation of the study
• \) Subjects with a history of hypersensitivity to probucol or cilostazol
• \) Subjects with homozygous familial hyperlipidemia\*
• \) Subjects with a triglyceride ( TG) level greater than 400mg/dL at screening
• \) Subjects with uncontrolled diabetes : HbA1c level greater than 9%
• \) Subjects with New York Heart Association (NYHA) classification: Class Ⅲ and Ⅳ
• \) Subjects with a QTc interval greater than 450msec(male) 470msec(female)
• \) Subjects with serious ventricular arrythmias (frequent episodes of multifocal ventricular extrasystole)
• \) Subjects with atrial fibrillation (including paroxysmal AF)
• \) Subjects with unstable angina
• \) Subjects with liver and kidney functions that satisfy the following criteria - AST or ALT \>100 IU/L, serum creatinine \>1.5 mg/dL
• \) Subjects who are participating in another clinical trial
• \) 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
• \) Subjects with clinically significant disorders of blood coagulation

Sponsors & Collaborators

• Seoul National University Hospital: lead
• Korea Otsuka Pharmaceutical Co., Ltd.: collaborator

Study Sites (5)

Dong-A Medical Center

Seogu, Busan, 602-715, South Korea

Location

Samsung Medical Center

Seoul, Gangnam-Gu, 135-710, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 463-707, South Korea

Location

Seoul National University Hospital

Seoul, 110-744, South Korea

Location

Boramae Medical Center

Seoul, 156-707, South Korea

Location

Related Publications (25)

• Manzato E. Scandinavian simvastatin study (4S). Lancet. 1994 Dec 24-31;344(8939-8940):1767; author reply 1767-8. No abstract available.

  PMID: 7997016 RESULT

• Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, Cuddy TE, Moye LA, Piller LB, Rutherford J, Simpson LM, Braunwald E. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators. Circulation. 1999 Jan 19;99(2):216-23. doi: 10.1161/01.cir.99.2.216.

  PMID: 9892586 RESULT

• Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998 Nov 5;339(19):1349-57. doi: 10.1056/NEJM199811053391902.

  PMID: 9841303 RESULT

• Barnhart JW, Sefranka JA, McIntosh DD. Hypocholesterolemic effect of 4,4'-(isopropylidenedithio)-bis(2,6-di-t-butylphenol) (probucol). Am J Clin Nutr. 1970 Sep;23(9):1229-33. doi: 10.1093/ajcn/23.9.1229. No abstract available.

  PMID: 5450842 RESULT

• 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. doi: 10.1016/0021-9150(81)90029-0.

  PMID: 6946776 RESULT

• 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. doi: 10.1254/jjp.40.123.

  PMID: 3959347 RESULT

• Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A, Yoshida H, Kawai C. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5928-31. doi: 10.1073/pnas.84.16.5928.

  PMID: 3475709 RESULT

• Ishigami M, Yamashita S, Sakai N, Hirano K, Arai T, Maruyama T, Takami S, Koyama M, Kameda-Takemura K, Matsuzawa Y. High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins. Eur J Clin Invest. 1997 Apr;27(4):285-92. doi: 10.1046/j.1365-2362.1997.1040657.x.

  PMID: 9134376 RESULT

• 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. doi: 10.1161/01.atv.19.5.1325.

  PMID: 10323786 RESULT

• 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;62(3):66B-72B. doi: 10.1016/s0002-9149(88)80055-9.

  PMID: 3394656 RESULT

• Daida H, Kuwabara Y, Yokoi H, Nishikawa H, Takatsu F, Nakata Y, Kutsumi Y, Oshima S, Nishiyama S, Ishiwata S, Kato K, Nishimura S, Miyauchi K, Kanoh T, Yamaguchi H. Effect of probucol on repeat revascularization rate after percutaneous transluminal coronary angioplasty (from the Probucol Angioplasty Restenosis Trial [PART]). Am J Cardiol. 2000 Sep 1;86(5):550-2, A9. doi: 10.1016/s0002-9149(00)01013-4.

  PMID: 11009277 RESULT

• Tardif JC, Cote G, Lesperance 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(6):365-72. doi: 10.1056/NEJM199708073370601.

  PMID: 9241125 RESULT

• Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 1995 Feb 23;332(8):488-93. doi: 10.1056/NEJM199502233320802.

  PMID: 7830729 RESULT

• 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 Am Coll Cardiol. 2002 Feb 20;39(4):610-6. doi: 10.1016/s0735-1097(01)01783-1.

  PMID: 11849859 RESULT

• Yamashita S, Bujo 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. J Atheroscler Thromb. 2008 Dec;15(6):292-303. doi: 10.5551/jat.e610. Epub 2008 Dec 6.

  PMID: 19060422 RESULT

• Bots ML, Grobbee DE. Intima media thickness as a surrogate marker for generalised atherosclerosis. Cardiovasc Drugs Ther. 2002 Jul;16(4):341-51. doi: 10.1023/a:1021738111273.

  PMID: 12652104 RESULT

• Crouse JR 3rd, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol. 1995 Mar 1;75(7):455-9. doi: 10.1016/s0002-9149(99)80580-3.

  PMID: 7863988 RESULT

• de Groot E, Jukema JW, Montauban van Swijndregt AD, Zwinderman AH, Ackerstaff RG, van der Steen AF, Bom N, Lie KI, Bruschke AV. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol. 1998 Jun;31(7):1561-7. doi: 10.1016/s0735-1097(98)00170-3.

  PMID: 9626835 RESULT

• MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H. Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation. 1998 May 12;97(18):1784-90. doi: 10.1161/01.cir.97.18.1784.

  PMID: 9603532 RESULT

• Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002 Oct 15;106(16):2055-60. doi: 10.1161/01.cir.0000034508.55617.65.

  PMID: 12379573 RESULT

• Baldassarre D, Franceschini G, Peruzzotti G, Brusoni B, Sirtori CR. Clinical evaluation of probucol in hypercholesteremia: individual lipoprotein responses and inhibitory effect on carotid atherosclerosis progression. J Cardiovasc Pharmacol. 1997 Dec;30(6):784-9. doi: 10.1097/00005344-199712000-00013.

  PMID: 9436818 RESULT

• Elam MB, Heckman J, Crouse JR, Hunninghake DB, Herd JA, Davidson M, Gordon IL, Bortey EB, Forbes WP. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol. 1998 Dec;18(12):1942-7. doi: 10.1161/01.atv.18.12.1942.

  PMID: 9848888 RESULT

• 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):473-8. doi: 10.1055/s-2008-1065348. Epub 2008 Apr 10.

  PMID: 18404599 RESULT

• 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 endothelial cells. Korean J Physiol Pharmacol. 2008 Aug;12(4):165-70. doi: 10.4196/kjpp.2008.12.4.165. Epub 2008 Aug 31.

  PMID: 19967051 RESULT

• Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001 Feb 24;357(9256):577-81. doi: 10.1016/s0140-6736(00)04053-8.

  PMID: 11558482 RESULT

MeSH Terms

Conditions

Hyperlipidemias

Interventions

Hydroxymethylglutaryl-CoA Reductase Inhibitors; Probucol; Cilostazol

Condition Hierarchy (Ancestors)

Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Byung-Hee Oh, M.D.

  Seoul National University Hospital

  STUDY CHAIR

• Cheol Ho Kim, M.D.

  Seoul National University Bundang Hospital

  PRINCIPAL INVESTIGATOR

• Sang-Hyun Kim, M.D.

  SMG-SNU Boramae Medical Center

  PRINCIPAL INVESTIGATOR

• Moo-Hyun Kim, M.D.

  Dong-A medical center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Internal Medicine/Cardiology

Study Record Dates

• First Submitted: January 31, 2011
• First Posted: February 8, 2011
• Study Start: March 1, 2011
• Primary Completion: December 1, 2016
• Study Completion: March 1, 2017
• Last Updated: September 20, 2019

Record last verified: 2019-09

Locations

KR (5)