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

Study Overview
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Brief Summary
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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.

Detailed Description
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Primary: 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. 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: 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. 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. 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. To assess the effect of drug withdrawal on these endpoints at follow-up (from Week 12 to Week 16). To explore the relationship between changes in FMD and changes in the biomarker levels at Week 12.

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

Conditions
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Peripheral Artery Disease

Intervention / Treatment
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* Drug: Cilostazol, Probucol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age is ≥ 40 and <80 years at Screening. The subject has a diagnosis of PAD The subject has a diagnosis of CAD Stable background medical therapy over the past 3 months Taking 100mg/day of aspirin or 75mg/day of clopidogrel over the past 3 months Hyperlipidemia defined as a LDL cholesterol concentration > 70 mg/dL The subject is willing to participate in this study as documented by written informed consent Exclusion Criteria: New diagnosis of PAD within 3 months. Currently taking cilostazol or has taken cilostazol Currently taking probucol or has taken probucol within the last 3 months Critical limb ischemia (CLI) Congestive heart failure Transient ischemic attack (TIA) Endovascular peripheral or coronary revascularization procedure within 3 months Coronary artery bypass graft (CABG) or major cardiovascular surgical procedures within 6 months Major surgical procedures within 3 months Uncontrolled hypertension Type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus Diabetic complications of severe peripheral neuropathy or active retinopathy. Inflammatory bowel disease. Unstable angina QT prolongation Severe or life threatening ventricular arrhythmias History of syncope Serum creatinine > 2.5 mg/dL, Creatinine Clearance ≤25ml/min or renal failure requiring dialysis. History or evidence of any hematological or clotting disorder. Hematocrit ≤ 28% or ≥ 55%. AST or ALT > 3 times the upper limit of normal (ULN). Any form of chronic anticoagulation. Coagulopathies defined as an INR > 1.5 History of malignant disease within 5 years. Acute or chronic hepatitis. Hemophilia or known increased risk of hemorrhage. Other clinically significant disorders resulting in a remaining life expectancy less than one year. Current alcohol or drug abuse. If female, the subject cannot be pregnant or breastfeeding and must be of non-childbearing potential

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 79 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Cilostazol, Probucol<br>* 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<br>|
| Experimental: Cilostazol<br>cilostazol | Drug: Cilostazol, Probucol<br>* 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<br>|
| Experimental: Probucol<br>probucol | Drug: Cilostazol, Probucol<br>* 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<br>|
| Experimental: Cilostazol + Probucol<br>cilostazol and probucol | Drug: Cilostazol, Probucol<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarker, Endothelial Function, Peripheral Artery Disease, Coronary Artery Disease, Flow Mediated Dilation, Cilostazol, Probucol