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

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ClinicalTrials.gov Identifier: NCT02174939
Recruitment Status : Unknown
Verified October 2015 by National Cheng-Kung University Hospital.
Recruitment status was:  Recruiting
First Posted : June 26, 2014
Last Update Posted : October 14, 2015
Sponsor:
Collaborator:
Department of Health, Executive Yuan, R.O.C. (Taiwan)
Information provided by (Responsible Party):
National Cheng-Kung University Hospital

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.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: Cilostazol Drug: Dummy Placebo Phase 4

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : February 2014
Estimated Primary Completion Date : October 2017
Estimated Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Cilostazol

Arm Intervention/treatment
Active Comparator: Cilostazol
One tablet (100 mg) twice per day for 12 weeks
Drug: Cilostazol
One tablet (100 mg) twice per day for 12 weeks
Other Name: Pletaal (brand name)

Placebo Comparator: Dummy Placebo
One tablet twice per day for 12 weeks
Drug: Dummy Placebo
One tablet twice per day for 12 weeks
Other Names:
  • Placebo
  • Control




Primary Outcome Measures :
  1. Circulating EPCs Number [ Time Frame: 3 months ]
    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 :
  1. Viability (Proliferation) of EPCs [ Time Frame: 3 months ]
    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.

  2. Composite Major Adverse Cardiovascular Events (MACE) [ Time Frame: at least 1 year ]
    This composite endpoint includes cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, congestive heart failure hospitalization, and target vessel revascularization.

  3. composite major coronary events [ Time Frame: at least 1 year ]
    This composite endpoint includes fatal or nonfatal myocardial infarction, recurrent angina pectoris, and target vessel revascularization.


Other Outcome Measures:
  1. FMD of the Brachial Artery [ Time Frame: 3 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02174939


Contacts
Contact: Ting-Hsing Chao, MD 886-6-2353535 ext 2382 chaoth@mail.ncku.edu.tw

Locations
Taiwan
National Cheng Kung University Hospital Recruiting
Tainan, Taiwan, 704
Contact: Ting-Hsing Chao, MD    886-6-2353535 ext 2382    chaoth@mail.ncku.edu.tw   
Principal Investigator: Ting-Hsing Chao, MD         
Sponsors and Collaborators
National Cheng-Kung University Hospital
Department of Health, Executive Yuan, R.O.C. (Taiwan)
Investigators
Principal Investigator: Ting-Hsing Chao, MD National Cheng-Kung University Hospital

Publications:
Responsible Party: National Cheng-Kung University Hospital
ClinicalTrials.gov Identifier: NCT02174939     History of Changes
Other Study ID Numbers: A-BR-102-076
NCKUH-10304022 ( Other Grant/Funding Number: NCKUH )
First Posted: June 26, 2014    Key Record Dates
Last Update Posted: October 14, 2015
Last Verified: October 2015

Keywords provided by National Cheng-Kung University Hospital:
cilostazol
progenitor cells
coronary artery disease
myocardial infarction
angiogenesis
biological markers
endothelial function

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cilostazol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Vasodilator Agents
Neuroprotective Agents
Protective Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors