Evaluation of Concomitant Administration of Cilostazol and Probucol on Biomarkers, Endothelial Function and Safety

Evaluation of Concomitant Administration of Cilostazol and Probucol on Biomarkers, Endothelial Function and Safety in Peripheral Artery Disease Subjects Complicated With Coronary Artery Disease.

Based upon evidence of efficacy and safety of both cilostazol and probucol administration in independent randomized controlled trials in PAD and CAD, the present trial seeks to investigate the effect of concomitant administration of cilostazol and probucol on FMD compared to each drug individually, as well as to evaluate biomarker measures and safety indices in this context.

Study Overview

• Status: Completed
• Conditions: Peripheral Artery Disease
• Intervention / Treatment: Drug: Cilostazol, Probucol

Detailed Description

Primary:

1. To evaluate the effect of concomitant administration of cilostazol and probucol on the 12-week change in FMD from baseline compared, with individual drugs alone.
2. To assess the safety of concomitant administration of cilostazol and probucol in peripheral artery disease (PAD) subjects complicated with coronary artery disease (CAD) as determined by physical examination, vital signs, adverse events (AEs), laboratory tests, ECGs.

Secondary:

1. To evaluate the effect of cilostazol and probucol administered concomitantly and as individual drugs, compared with control, on changes in FMD from baseline to Weeks 6 and 12.
2. To evaluate the effect of cilostazol and probucol administered concomitantly and as individual drugs, compared with control, on changes in metabolic, inflammatory, oxidative, and platelet biomarkers from baseline to Weeks 6 and 12.
3. To evaluate the effect of cilostazol and probucol administered concomitantly and as individual drugs, compared with control, on the time course (over the 12-week treatment period) of changes in FMD and biomarkers levels.
4. To assess the effect of drug withdrawal on these endpoints at follow-up (from Week 12 to Week 16).
5. To explore the relationship between changes in FMD and changes in the biomarker levels at Week 12.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age is ≥ 40 and <80 years at Screening.
2. The subject has a diagnosis of PAD
3. The subject has a diagnosis of CAD
4. Stable background medical therapy over the past 3 months
5. Taking 100mg/day of aspirin or 75mg/day of clopidogrel over the past 3 months
6. Hyperlipidemia defined as a LDL cholesterol concentration > 70 mg/dL
7. The subject is willing to participate in this study as documented by written informed consent

Exclusion Criteria:

1. New diagnosis of PAD within 3 months.
2. Currently taking cilostazol or has taken cilostazol
3. Currently taking probucol or has taken probucol within the last 3 months
4. Critical limb ischemia (CLI)
5. Congestive heart failure
6. Transient ischemic attack (TIA)
7. Endovascular peripheral or coronary revascularization procedure within 3 months
8. Coronary artery bypass graft (CABG) or major cardiovascular surgical procedures within 6 months
9. Major surgical procedures within 3 months
10. Uncontrolled hypertension
11. Type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus
12. Diabetic complications of severe peripheral neuropathy or active retinopathy.
13. Inflammatory bowel disease.
14. Unstable angina
15. QT prolongation
16. Severe or life threatening ventricular arrhythmias
17. History of syncope
18. Serum creatinine > 2.5 mg/dL, Creatinine Clearance ≤25ml/min or renal failure requiring dialysis.
19. History or evidence of any hematological or clotting disorder.
20. Hematocrit ≤ 28% or ≥ 55%.
21. AST or ALT > 3 times the upper limit of normal (ULN).
22. Any form of chronic anticoagulation.
23. Coagulopathies defined as an INR > 1.5
24. History of malignant disease within 5 years.
25. Acute or chronic hepatitis.
26. Hemophilia or known increased risk of hemorrhage.
27. Other clinically significant disorders resulting in a remaining life expectancy less than one year.
28. Current alcohol or drug abuse.
29. If female, the subject cannot be pregnant or breastfeeding and must be of non-childbearing potential

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Cilostazol, Probucol; Treatment Group 1 (control) No cilostazol or probucol Treatment Group 2 (cilostazol alone) 1 tablet cilostazol 100 mg PO BID Treatment Group 3 (probucol alone) 1 tablet probucol 250 mg PO BID Treatment Group 4 (concomitant cilostazol and probucol) 1 tablet cilostazol 100 mg PO BID, and 1 tablet probucol 250 mg PO BID
EXPERIMENTAL: Cilostazol; cilostazol	Drug: Cilostazol, Probucol; Treatment Group 1 (control) No cilostazol or probucol Treatment Group 2 (cilostazol alone) 1 tablet cilostazol 100 mg PO BID Treatment Group 3 (probucol alone) 1 tablet probucol 250 mg PO BID Treatment Group 4 (concomitant cilostazol and probucol) 1 tablet cilostazol 100 mg PO BID, and 1 tablet probucol 250 mg PO BID
EXPERIMENTAL: Probucol; probucol	Drug: Cilostazol, Probucol; Treatment Group 1 (control) No cilostazol or probucol Treatment Group 2 (cilostazol alone) 1 tablet cilostazol 100 mg PO BID Treatment Group 3 (probucol alone) 1 tablet probucol 250 mg PO BID Treatment Group 4 (concomitant cilostazol and probucol) 1 tablet cilostazol 100 mg PO BID, and 1 tablet probucol 250 mg PO BID
EXPERIMENTAL: Cilostazol + Probucol; cilostazol and probucol	Drug: Cilostazol, Probucol; Treatment Group 1 (control) No cilostazol or probucol Treatment Group 2 (cilostazol alone) 1 tablet cilostazol 100 mg PO BID Treatment Group 3 (probucol alone) 1 tablet probucol 250 mg PO BID Treatment Group 4 (concomitant cilostazol and probucol) 1 tablet cilostazol 100 mg PO BID, and 1 tablet probucol 250 mg PO BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
On the 12-week change in FMD / Safety	To evaluate the effect of concomitant administration of cilostazol and probucol on the 12-week change; To assess the safety of concomitant administration of cilostazol and probucol	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the biomarker and FMD	To evaluate the effect of cilostazol and probucol administered concomitantly and as individual drugs, compared with control, on changes in FMD; To evaluate the effect of cilostazol and probucol administered concomitantly and as individual drugs, compared with control on biomarkers; To evaluate the effect of cilostazol and probucol administered concomitantly and as individual drugs, compared with control, on the time course; To assess the effect of drug withdrawal; To explore the relationship between changes in FMD and changes in the biomarker levels	12 weeks

Collaborators and Investigators

• Sponsor: Korea Otsuka Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 19, 2010
• Primary Completion (ACTUAL): November 29, 2012
• Study Completion (ACTUAL): December 18, 2012

Study Registration Dates

• First Submitted: June 10, 2010
• First Submitted That Met QC Criteria: June 10, 2010
• First Posted (ESTIMATE): June 11, 2010

Study Record Updates

• Last Update Posted (ACTUAL): July 18, 2022
• Last Update Submitted That Met QC Criteria: July 14, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Biomarker; Coronary Artery Disease; Endothelial Function; Peripheral Artery Disease; Cilostazol; Flow Mediated Dilation; Probucol
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Vascular Diseases; Peripheral Arterial Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Antimetabolites; Neuroprotective Agents; Protective Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Cilostazol; Probucol
• Other Study ID Numbers: 021-KOA-0901i