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Effect of Cilostazol Endothelial Progenitor Cells and Collateral Formation in Peripheral Occlusive Artery Disease (PAOD)

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ClinicalTrials.gov Identifier: NCT01952756
Recruitment Status : Completed
First Posted : September 30, 2013
Last Update Posted : July 18, 2014
Sponsor:
Collaborator:
Department of Health, Executive Yuan, R.O.C. (Taiwan)
Information provided by (Responsible Party):
National Cheng-Kung University Hospital

Tracking Information
First Submitted Date  ICMJE September 21, 2013
First Posted Date  ICMJE September 30, 2013
Last Update Posted Date July 18, 2014
Study Start Date  ICMJE January 2012
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 25, 2013)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2013)
Colony Formation by EPCs [ Time Frame: 3 months ]
Peripheral blood mononuclear cells are isolated by density gradient centrifugation according to standard protocols. After centrifugation, cells are washed, resuspended in M199 medium supplemented with 20% (vol/vol) fetal bovine serum, 10 ng/ml vascular endothelial growth factor, 2 ng/ml basic-fibroblast growth factor, 10 ng/ml epidermal growth factor and 2 ng/ml insulin growth factor, and cultured in 24-well plates coated with human fibronectin for 7 days. EPCs cells are confirmed by uptake of acetyl-low density lipoprotein and lectin and by the expression of EPC markers. Cells are harvested after 7 days, fixed and stained with crystal violet reagent. The colony densities are quantified with an Olympus microscope at 100-fold magnification using an imaging measurement software.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 25, 2013)
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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Effect of Cilostazol Endothelial Progenitor Cells and Collateral Formation in Peripheral Occlusive Artery Disease (PAOD)
Official Title  ICMJE 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
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Peripheral Arterial Diseases
Intervention  ICMJE
  • Drug: Cilostazol
    One tablet (100 mg) twice per day for 12 weeks
    Other Name: Pletaal (brand name)
  • Drug: Dummy Placebo
    One tablet twice per day for 12 weeks
    Other Names:
    • Placebo
    • Control
Study Arms  ICMJE
  • Active Comparator: Cilostazol
    One tablet (100 mg) twice per day for 12 weeks
    Intervention: Drug: Cilostazol
  • Placebo Comparator: Dummy Placebo
    One tablet twice per day for 12 weeks
    Intervention: Drug: Dummy Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 25, 2013)
44
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE September 2013
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01952756
Other Study ID Numbers  ICMJE NCKUH-10103043/BR-100-134
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cheng-Kung University Hospital
Study Sponsor  ICMJE National Cheng-Kung University Hospital
Collaborators  ICMJE Department of Health, Executive Yuan, R.O.C. (Taiwan)
Investigators  ICMJE
Principal Investigator: Ting-Hsing Chao, MD National Cheng-Kung University Hospital
PRS Account National Cheng-Kung University Hospital
Verification Date July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP