DORIC: Diabetic Artery Obstruction: is it Possible to Reduce Ischemic Events With Cilostazol?

Sponsor

University of Ioannina (Other)

Overall Status

Completed

CT.gov ID

NCT02983214

Collaborator

LIBYTEC Pharmaceutical S.A. (Other)

826

Enrollment

Location

Arms

Actual Duration (Months)

23.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Investigation of the clinical efficacy and safety of dual antiplatelet therapy with clopidogrel and cilostazol versus clopidogrel alone in preventing ischemic vascular events in patients with type 2 diabetes and symptomatic peripheral arterial disease.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke Peripheral Artery Disease Diabetes Mellitus, Type 2	Drug: Clopidogrel Drug: Cilostazol	Phase 4

Detailed Description

Cilostazol is a quinoline derivative that selectively and reversibly inhibits cellular cyclic adenosine monophosphate (cAMP) phosphodiesterase III, thus suppressing cAMP degradation and maintaining its high intracellular levels. Through this mechanism, cilostazol inhibits platelet aggregation, exerting significant antiplatelet and antithrombotic activity. Cilostazol also improves endothelial function and exerts anti-inflammatory, anti-atherogenic and vasodilatory effects. Additionally, cilostazol inhibits equilibrative nucleoside transporter-1 (ENT-1) which is responsible for the cellular uptake of adenosine, reducing its plasma concentration. Through this mechanism, cilostazol maintains high extracellular adenosine concentration allowing adenosine to exert its biological effects. Thus, cilostazol not only shows potent antithrombotic activity, but also prevents restenosis after percutaneous coronary intervention (PCI). Finally, cilostazol has beneficial effects in the lipidemic profile reducing triglyceride levels and increasing HDL-cholesterol. Clinical studies have shown that in patients with intermittent claudication, cilostazol increases the walking distance. Based on these studies, cilostazol administration in combination with an antiplatelet drug (clopidogrel or aspirin) is recommended for patients with intertermittent claudication.

Recent pharmacodynamic studies have demonstrated that adding cilostazol to aspirin or clopidogrel may represent an effective way to overcome high on-treatment platelet reactivity. Additionally, clinical studies have shown that the addition of cilostazol to dual antiplatelet therapy with aspirin and clopidogrel (triple antiplatelet therapy, TAPT) in patients with acute coronary syndrome undergoing PCI offers significant clinical benefit. This favorable effect of cilostazol was confirmed in a recent meta-analysis which included nine studies and a total of 2,179 patients undergoing PCI. Furthermore, other clinical studies have shown that administration of TAPT with cilostazol reduces restenosis after PCI. Finally, the administration of dual antiplatelet therapy with cilostazol and aspirin significantly reduces the progression of symptomatic intracranial arterial stenosis compared to monotherapy with aspirin.

The aim of The Diabetic artery Obstruction: is it possible to Reduce Ischemic events with Cilostazol? (DORIC) trial is to investigate the clinical efficacy and safety of dual antiplatelet therapy (DAPT) with clopidogrel and cilostazol versus clopidogrel alone in preventing ischemic vascular eventsin patients with type 2 diabetes (DM2) and symptomatic peripheral arterial disease (PAD).

Study Design

Study Type:

Interventional

Actual Enrollment :

826 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Health Services Research

Official Title:

Study of the Efficacy and Safety of Cilostazol in the Prevention of Ischemic Vascular Events in Diabetic Patients With Symptomatic Peripheral Artery Disease.

Actual Study Start Date :

Nov 1, 2016

Actual Primary Completion Date :

Oct 1, 2019

Actual Study Completion Date :

Oct 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clopidogrel Clopidogrel 75 mg/day	Drug: Clopidogrel Other Names: Plavix, Clodelib, Clovelen
Active Comparator: Clopidogrel plus cilostazol Clopidogrel 75 mg/day plus cilostazol 100 mg twice/day	Drug: Clopidogrel Other Names: Plavix, Clodelib, Clovelen Drug: Cilostazol Other Names: Claudiasil

Arm

Intervention/Treatment

Active Comparator: Clopidogrel

Clopidogrel 75 mg/day

Drug: Clopidogrel

Other Names:

Plavix, Clodelib, Clovelen

Active Comparator: Clopidogrel plus cilostazol

Clopidogrel 75 mg/day plus cilostazol 100 mg twice/day

Drug: Clopidogrel

Other Names:

Plavix, Clodelib, Clovelen

Drug: Cilostazol

Other Names:

Claudiasil

Outcome Measures

Primary Outcome Measures

Number of participants who suffer from the primary efficacy end point which is composite of acute ischemic stroke/transient ischemic attack (TIA), myocardial infarction (MI), or death from vascular causes during the entire follow-up period. [12 months]
Death from vascular causes: cardiovascular or cerebrovascular
Number of participants who suffer from bleeding events as defined by the Bleeding Academic Research Consortium (BARC) criteria during the entire follow-up period. [12 months]

Secondary Outcome Measures

Number of participants whose major secondary efficacy end point desribed in the description section is observed. [12 months]
Acute ischemic stroke / TIA, AMI, coronary stent thrombosis, PCI, coronary restenosis, death from cardiovascular causes, death from any cause, hospitalization for acute limb ischemia, lower extremity arterial revascularization, improvement of ABI and pain-free walking distance values.
Number of participants who suffer from the secondary safety end points which are palpitations, tachycardia, headache, diarrhea, urticaria, neoplasms, blood disorders, drug interruption. [12 months]
Blood disorders: transient thrombocytopenia, leukopenia

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients aged ≥50 years with DM2 and symptomatic PAD diagnosed clinically (according to Fontaine criteria, stage IIa or IIb and III) and by measuring the ΑΒΙ.

Exclusion Criteria:

Congestive heart failure, history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular extrasystoles or QTc prolongation.
Patients with atrial fibrillation taking any anticoagulant therapy or patients with a history of cardioembolic ischemic stroke or hemorrhagic stroke.
Patients with a history (≤ 12 months) of acute coronary syndrome receiving dual antiplatelet therapy, or patients receiving monotherapy with aspirin.
Patients with hepatic impairment (child-Pugh staging, calibration ≥ 5) or renal impairment (creatinine clearance ≤ 30ml / min), recent peptic ulcer, a history of hypersensitivity to cilostazol, cancer patients undergoing treatment.