Clinical trial NCT01952756: Effect of Cilostazol Endothelial Progenitor Cells and Collateral Formation in Peripheral Occlusive Artery Disease (PAOD)
Official title: Cilostazol Enhances the Number and Functions of Circulating Endothelial Progenitor Cells and Collateral Formation Assessed by Dual-energy 128-row CT Angiography Mediated Through Multiple Mechanisms in Patients With Mild-to-moderate PAOD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Peripheral Arterial Diseases
Keywords: cilostazol
endothelial progenitor cells
vasculogenesis
angiogenesis
peripheral arterial disease
biomarkers
Lead sponsor: National Cheng-Kung University Hospital
Sponsor class: OTHER
Collaborators: name: Department of Health, Executive Yuan, R.O.C. (Taiwan)
First posted: 2013-09-30
Enrollment: 44
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 PAOD.
2. This double-blind, randomized, placebo-controlled trial to evaluate the effects of cilostazol on human early EPCs and angiogenesis as well as the potential mechanisms of action in patients with mild-to-moderate PAOD.

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

      * 24 subjects with cilostazol and 20 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. collateral vessels formation and distal run-off assessed by dual-energy multi-slice computed tomography angiography
4. echocardiographic examinations to evaluate left ventricular functions

Eligibility criteria: Inclusion Criteria:

* ankle-brachial index (ABI) less than 0.9 in one or both legs but no obvious symptoms of intermittent claudication

Exclusion Criteria:

* obvious symptoms of intermittent claudication
* severe PAD (Fontaine grading \> 3) or critical limb ischemia in at least one leg
* severe liver dysfunction (transaminases \>10 times of upper normal limit, history of liver cirrhosis, or hepatoma)
* \> stage 4 chronic kidney disease (end-stage renal disease with chronic dialysis not excluded)
* left ventricular ejection fraction \<50% by echocardiography
* documented active malignancy
* chronic inflammatory disease
* planned coronary intervention or endovascular therapy or bypass surgery within 3 months
* 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: Colony Formation by EPCs
timeFrame: 3 months
Other outcomes:
measure: Viability (Proliferation) of EPCs
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, 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.