Clinical trial NCT02174939: Effect of Cilostazol on Endothelial Progenitor Cells and Endothelial Function in Coronary Artery Disease
Official title: Cilostazol Enhances the Number and Functions of Circulating Endothelial Progenitor Cells and Endothelial Function Mediated Through Modification of Vasculogenesis and Angiogenesis Factors in Patients With Stable Coronary Artery Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Coronary Artery Disease
Keywords: cilostazol
progenitor cells
coronary artery disease
myocardial infarction
angiogenesis
biological markers
endothelial function
Lead sponsor: National Cheng-Kung University Hospital
Sponsor class: OTHER
Collaborators: name: Department of Health, Executive Yuan, R.O.C. (Taiwan)
First posted: 2014-06-26
Enrollment: 300
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 1. The number and function of circulating endothelial progenitor cells (EPCs) are inversely associated with coronary risk factors and atherosclerotic diseases such as coronary artery disease (CAD) and cardiovascular high risk.
2. This double-blind, randomized, placebo-controlled trial to evaluate the effects of cilostazol on human early EPCs and endothelial function as well as the potential mechanisms of action in patients with CAD and cardiovascular high risk.

Detailed description: 1. titration of drugs

   1. run-in period: eligible subjects are screened and baseline blood samples are obtained
   2. study period: 12 weeks

      * subjects with cilostazol and subjects with dummy placebo
      * On the first day after the end of the study period, the follow-up data are obtained by the same procedure
   3. blood sampling and measurement of serum biomarkers

      * obtained from peripheral veins in all study subjects at the run-in period and the end of the treatment period of the study
      * sent for isolation, cell culture, and assays of human EPCs
      * also stored for enzyme-linked immunosorbent assay (Stromal cell derived factor-alfa1, adiponectin, soluble thrombomodulin, vascular endothelial growth factor)
2. assays of human EPCs

   1. colony formation by EPCs
   2. quantification of EPCs and apoptotic endothelial cells
   3. chemotactic motility, proliferation/viability and apoptosis assays
3. measurement of flow-mediated dilatation (FMD) of left brachial artery by sonography
4. assessment of long-term cardiovascular outcomes

Eligibility criteria: Inclusion Criteria:

* stable CAD documented by stress test, computed tomography angiography or coronary angiography or
* old myocardial infarction (\>6 months)
* history and evidence of CAD
* history and evidence of cerebrovascular accident
* history and evidence of peripheral artery disease
* diabetes mellitus
* metabolic syndrome
* stage 3 to 5 chronic kidney disease
* at least 2 of the followings: male ≥45 years old or female ≥55 years old; hypertension; current or past 3-year tobacco smoking; hyperlipidemia; family history of premature CAD (male \<55 years old or female \<65 years old)

Exclusion Criteria:

* unstable CAD
* have plan to do percutaneous intervention or bypass surgery for CAD or peripheral artery disease within recent 3 months
* severe liver dysfunction (transaminases \>10 times of upper normal limit, history of liver cirrhosis, or hepatoma)
* left ventricular ejection fraction (\<50% by echocardiography)
* documented active malignancy
* chronic inflammatory disease
* known drug allergy history for cilostazol
* current use of cilostazol or any other cAMP-elevator
* premenopausal women

Primary outcomes:
measure: Circulating EPCs Number
timeFrame: 3 months
Secondary outcomes:
measure: Viability (Proliferation) of EPCs
timeFrame: 3 months
measure: Composite Major Adverse Cardiovascular Events (MACE)
timeFrame: at least 1 year
measure: composite major coronary events
timeFrame: at least 1 year
Other outcomes:
measure: FMD of the Brachial Artery
timeFrame: 3 months
Locations:
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
Study officials:
affiliation: National Cheng-Kung University Hospital
name: Ting-Hsing Chao, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chao TH, Tseng SY, Li YH, Liu PY, Cho CL, Shi GY, Wu HL, Chen JH. A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade. Clin Sci (Lond). 2012 Aug 1;123(3):147-59. doi: 10.1042/CS20110432.
citation: Biscetti F, Pecorini G, Straface G, Arena V, Stigliano E, Rutella S, Locatelli F, Angelini F, Ghirlanda G, Flex A. Cilostazol promotes angiogenesis after peripheral ischemia through a VEGF-dependent mechanism. Int J Cardiol. 2013 Aug 10;167(3):910-6. doi: 10.1016/j.ijcard.2012.03.103. Epub 2012 Apr 2.
citation: Chao TH, Tseng SY, Chen IC, Tsai YS, Huang YY, Liu PY, Ou HY, Li YH, Wu HL, Cho CL, Tsai LM, Chen JH. Cilostazol enhances mobilization and proliferation of endothelial progenitor cells and collateral formation by modifying vasculo-angiogenic biomarkers in peripheral arterial disease. Int J Cardiol. 2014 Mar 15;172(2):e371-4. doi: 10.1016/j.ijcard.2013.12.295. Epub 2014 Jan 11. No abstract available.