Clinical trial NCT02194686: Effect of Cilostazol on Endothelial Progenitor Cells and Endothelial Function in High Risk for Cardiovascular Disease
Official title: Cilostazol Enhances the Number and Functions of Circulating Endothelial Progenitor Cells Mediated Through Multiple Mechanisms in Patients With High Risk for Cardiovascular Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cardiovascular Diseases
Keywords: cilostazol
progenitor cells
cardiovascular disease
risk factors
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: 2014-07-18
Enrollment: 71
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.
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 high risk for cardiovascular disease.

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

Eligibility criteria: Inclusion Criteria: high-risk patients who have at least one of the following situations without pre-existing cardiovascular disease including peripheral artery disease or coronary artery disease:

* type 2 diabetes mellitus
* metabolic syndrome
* stage 3 (or more advanced) chronic kidney disease
* 2 or more coronary risk factors (male \> 45 years or female \> 55 years, hypertension, tobacco smoking, hyperlipidemia, family history of cardiovascular disease)

Exclusion Criteria:

* ankle-brachial index less than 0.9 or more than 1.3 in one or both legs
* significant stenosis (more than 50% as compared to reference vessel) in peripheral artery on image study
* symptoms suggesting peripheral artery disease in at least one leg
* clinical or electrocardiographic evidence of coronary artery disease
* clinical evidence of cerebrovascular disease
* 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
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.
citation: Chao TH, Chen IC, Li YH, Lee PT, Tseng SY. Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Elevated in Patients With Peripheral Artery Disease and Associated With Metabolic Disorders and Dysfunction in Circulating Progenitor Cells. J Am Heart Assoc. 2016 May 20;5(5):e003497. doi: 10.1161/JAHA.116.003497.