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Effect of Cilostazol on Endothelial Progenitor Cells and Endothelial Function in Coronary Artery Disease

Primary Purpose

Coronary Artery Disease

Status

Unknown status

Phase

Phase 4

Locations

Taiwan

Study Type

Interventional

Intervention

Cilostazol

Dummy Placebo

About this trial

This is an interventional treatment trial for Coronary Artery Disease focused on measuring cilostazol, progenitor cells, coronary artery disease, myocardial infarction, angiogenesis, biological markers, endothelial function

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

National Cheng Kung University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Cilostazol

Dummy Placebo

Arm Description

One tablet (100 mg) twice per day for 12 weeks

One tablet twice per day for 12 weeks

Outcomes

Primary Outcome Measures

Circulating EPCs Number

Peripheral blood mononuclear cells (one million cells in each) are suspended in 100 µL phosphate-buffered saline and incubated for 30 min with monoclonal antibodies against human peridinin chlorophyll protein-conjugated cluster of differentiation antigen-45, phycoerythrin-conjugated anti-human cluster of differentiation antigen-34 antibody and anti-human kinase insert domain receptor (KDR) antibody conjugated with Alexa Flour 647. Cells are washed and analyzed on a FACSCalibur flow cytometer with 100,000 events in the lymphocyte gate. EPCs, which are defined as negative for cluster of differentiation antigen-45 and positive for cluster of differentiation antigen-34 and KDR. Based on the peripheral blood mononuclear cell counts, the absolute number of circulating EPCs/µL is calculated.

Secondary Outcome Measures

Viability (Proliferation) of EPCs

250,000 cells are seeded in each well of a 96-well plate and the cells are added with 200 μl of the culture medium and incubated at 37°C. Medium change is performed 3 days later. On 7th day, the plate is then re-incubated with 100 μl fresh medium and additional 50 μl of 2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2 Hydrogen-Tetrazolium-5-Carboxanilide reagent, and further incubated in dark at 37°C for 4 h. After incubation, the orange colored complex formed is read at 450 nm using a microplate reader with a 450 nm reference filter.

Composite Major Adverse Cardiovascular Events (MACE)

This composite endpoint includes cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, congestive heart failure hospitalization, and target vessel revascularization.

composite major coronary events

This composite endpoint includes fatal or nonfatal myocardial infarction, recurrent angina pectoris, and target vessel revascularization.

Full Information

NCT ID

NCT02174939

First Posted

June 22, 2014

Last Updated

October 11, 2015

Sponsor

National Cheng-Kung University Hospital

Collaborators

Department of Health, Executive Yuan, R.O.C. (Taiwan)

1. Study Identification

Unique Protocol Identification Number

NCT02174939

Brief Title

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

2. Study Status

Record Verification Date

October 2015

Overall Recruitment Status

Unknown status

Study Start Date

February 2014 (undefined)

Primary Completion Date

October 2017 (Anticipated)

Study Completion Date

December 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Cheng-Kung University Hospital

Collaborators

Department of Health, Executive Yuan, R.O.C. (Taiwan)

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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. 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

titration of drugs run-in period: eligible subjects are screened and baseline blood samples are obtained 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 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) assays of human EPCs colony formation by EPCs quantification of EPCs and apoptotic endothelial cells chemotactic motility, proliferation/viability and apoptosis assays measurement of flow-mediated dilatation (FMD) of left brachial artery by sonography assessment of long-term cardiovascular outcomes

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Coronary Artery Disease

Keywords

cilostazol, progenitor cells, coronary artery disease, myocardial infarction, angiogenesis, biological markers, endothelial function

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cilostazol

Arm Type

Active Comparator

Arm Description

One tablet (100 mg) twice per day for 12 weeks

Arm Title

Dummy Placebo

Arm Type

Placebo Comparator

Arm Description

One tablet twice per day for 12 weeks

Intervention Type

Drug

Intervention Name(s)

Cilostazol

Other Intervention Name(s)

Pletaal (brand name)

Intervention Description

One tablet (100 mg) twice per day for 12 weeks

Intervention Type

Drug

Intervention Name(s)

Dummy Placebo

Other Intervention Name(s)

Placebo, Control

Intervention Description

One tablet twice per day for 12 weeks

Primary Outcome Measure Information:

Title

Circulating EPCs Number

Description

Time Frame

3 months

Secondary Outcome Measure Information:

Title

Viability (Proliferation) of EPCs

Description

Time Frame

3 months

Title

Composite Major Adverse Cardiovascular Events (MACE)

Description

This composite endpoint includes cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, congestive heart failure hospitalization, and target vessel revascularization.

Time Frame

at least 1 year

Title

composite major coronary events

Description

This composite endpoint includes fatal or nonfatal myocardial infarction, recurrent angina pectoris, and target vessel revascularization.

Time Frame

at least 1 year

Other Pre-specified Outcome Measures:

Title

FMD of the Brachial Artery

Description

FMD in response to reactive hyperemia is measured in the left brachial artery in a quiet, temperature-controlled room after 10 min of bed rest. A high-resolution ultrasound machine equipped with a 7.5 mega Hertz linear array probe is used for the study. Arterial diameters are measured at the baseline and during reactive hyperemia. FMD is calculated as the percentage change in diameter compared with the baseline.

Time Frame

3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ting-Hsing Chao, MD

Phone

886-6-2353535

Ext

2382

chaoth@mail.ncku.edu.tw

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ting-Hsing Chao, MD

Organizational Affiliation

National Cheng-Kung University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Cheng Kung University Hospital

City

Tainan

ZIP/Postal Code

704

Country

Taiwan

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ting-Hsing Chao, MD

Phone

886-6-2353535

Ext

2382

chaoth@mail.ncku.edu.tw

First Name & Middle Initial & Last Name & Degree

Ting-Hsing Chao, MD

12. IPD Sharing Statement

Citations:

PubMed Identifier

22339730

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.

Results Reference

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PubMed Identifier

22473072

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.

Results Reference

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PubMed Identifier

24439864

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.

Results Reference

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Effect of Cilostazol on Endothelial Progenitor Cells and Endothelial Function in Coronary Artery Disease

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