Atherosclerosis, Cerebral Infarction
Conditions
Keywords
Infarction, Cerebral, cilostazol, stenosis, atherosclerosis, clopidogrel
Brief summary
This study will recruit 480 acute stroke patients with symptomatic intracranial stenosis (M1 segment of Middle cerebral artery (MCA) or basilar artery). They will be randomly assigned into cilostazol group or clopidogrel group. Every patients will take 100mg of aspirin a day additionally. The primary outcome variable of this study is Progression rate of symptomatic intracranial stenosis on magnetic resonance angiogram (MRA).
Detailed description
\[Goal\] To Reveal the Effect and Safety of Cilostazol Compared with Clopidogrel on the Prevention of the Progression of Symptomatic Intracranial Arterial Stenosis. \[Trial Design\] Double-Blind, Active-Controlled, Randomized, Multicenter Trial \[Participants\] Acute ischemic stroke patients with symptomatic intracranial arterial stenosis \[Methods\] * Double-Blind, Active-Controlled, Randomized, Multicenter Trial * Investigational product (Double Dummy Method): Cilostazol 200mg (100mg twice per day) versus clopidogrel 75mg * Concomitant medication: Aspirin 100 (75-150) mg per day * Medication Duration: 7 months \[Outcome Variables\] Primary Outcome Variable: * Progression rate of symptomatic intracranial arterial stenosis Secondary outcome variables: * The occurrence of new MRI (magnetic resonance image) lesion on follow-up MRI * Stroke events * Overall cardiovascular events: stroke, acute coronary syndrome, vascular death * Ipsilateral ischemic stroke rate * Fatal or major bleeding complications
Interventions
DRUGclopidogrel
Clopidogrel 75mg once a day plus placebo of cilostazol twice a day
DRUGCilostazol
Cilostazol 100mg twice a day plus placebo of clopidogrel once a day
Sponsors
Korea Otsuka International Asia Arab
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cerebral infarction within 2 weeks from the onset or TIA with corresponding acute ischemic brain lesions on MRI within 2 weeks from the onset * Age: more than 35 years of age * Patient with significant focal stenosis in the M1 segment of middle cerebral artery (MCA) or basilar artery (BA) with acute ischemic lesions on magnetic resonance imaging (MRI) within the vascular territory of the stenosed artery.
Exclusion criteria
* Patients with any contraindications to the treatment with antiplatelet therapy * Patients with potential cardiac embolic source; prosthetic valve, atrial fibrillation, atrial flutter, left atrial/atrial appendage thrombus, sick sinus syndrome, left ventricular thrombus, dilated cardiomyopathy, akinetic or hypokinetic left ventricular segment, atrial myxoma, Infective endocarditis, mitral valve stenosis or prolapse, mitral annuls calcification, left atrial turbulence, nonbacterial endocarditis, congestive heart failure, recent myocardial infarction (within 4 weeks) * Patients with more than 50% stenosis in the parent artery of symptomatic stenosis * Bleeding diathesis * Chronic liver disease (ALT \> 100 or AST \> 100) or chronic renal disease (creatinine \> 3.0mg/dl) * Anemia (hemoglobin \< 10mg/dl) or thrombocytopenia (platelet count less than 100,000/mm3) * Nonatherosclerotic vasculopathy; patients with clinical characteristics suggesting arterial dissection, moyamoya disease, Takayasu's arteritis, radiation associated angiopathy, and other vasculitis. * Severe stroke: NIH stroke scale : more than 16 * Pregnant or lactating patients * Chronic user of NSAIDs * Thrombolytic therapy for the symptomatic stenosis * Symptomatic stenosis scheduled for angioplasty * Patients with pacemaker or any other contraindications to MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression of Symptomatic Intracranial Stenosis | 7 months after treatment | Blind reviewers classified the presence and severity of stenosis on middle cerebral arteries and basilar artery on magnetic resonance angiogram (MRA) into 5 grades; normal, mild, moderate, severe and occlusion. Progression was defined as worsening of stenosis by 1 or more grades on final MRA as compared with the baseline MRA. The progression of symptomatic stenosis is defined as 1 or more grade worsening of the stenosis on the symptomatic artery on MRA. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Stroke Events | upto 7 months after randomization | including nonfatal ischemic stroke, nonfatal hemorrhagic stroke and fatal stroke |
| Number of Participants With Overall Cardiovascular Events | upto 7 months after randomization | including nonfatal stroke, nonfatal myocardial infarction and vascular death. |
| Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI | 7 months after treatment | number of patients with new ischemic lesions on FLAIR (Fluid attenuation inversion recovery) images of follow-up MRI, which were determined by slice to slice comparison with baseline MRI. |
| Number of Patients With Ipsilateral Ischemic Stroke Rate | upto 7 months after randomization | ischemic stroke event which occured in the vascular territory of initial symptomatic stenosis |
| Numbers of Fatal or Major Bleeding Complications | upto 7 months after randomization | life-threatening or fatal bleeding was defined as any fatal bleeding event, a drop in hemoglobin of ≥ 50g/L, or significant hypotension with need for inotropic agents, symptomatic intracranial hemorrhage, or transfusion of ≥ 4 units of red-blood cells or equivalent amount of whole blood. Major bleeding was defined as significantly disabling bleedings, intraocular bleeding leading to significant visual loss, or bleeding requiring transfusion of ≤ 3 units of red-blood cells or equivalent amount of whole blood |
Countries
Hong Kong, Philippines, South Korea, Thailand
Participant flow
Recruitment details
507 patients were registered www.toss2.com from 20 centers of 4 countries (Korea, Hongkong, Thailand, Philippines). 50 patients were excluded during case verification process because they did not satisfy patient's eligibility criteria. finally 457 patients were randomized into cilostazol or clopidogrel group
Pre-assignment details
The excluded patients did not satisfy the definition of the symptomatic stenosis of our study protocol.
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol cilostazol 100mg twice a day plus placebo of clopidogrel | 232 |
| Clopidogrel clopidogrel 75mg per day and matching placebo of cilostazol | 225 |
| Total | 457 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | clinical events without follow up MRI | 5 | 4 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 11 |
Baseline characteristics
| Characteristic | Total | Clopidogrel | Cilostazol |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 252 Participants | 113 Participants | 139 Participants |
| Age, Categorical Between 18 and 65 years | 205 Participants | 112 Participants | 93 Participants |
| Age Continuous | 65.52 years STANDARD_DEVIATION 11.24 | 64.58 years STANDARD_DEVIATION 11.11 | 66.42 years STANDARD_DEVIATION 11.33 |
| Region of Enrollment Hong Kong | 23 participants | 12 participants | 11 participants |
| Region of Enrollment Korea, Republic of | 413 participants | 203 participants | 210 participants |
| Region of Enrollment Philippines | 10 participants | 5 participants | 5 participants |
| Region of Enrollment Thailand | 11 participants | 5 participants | 6 participants |
| Sex: Female, Male Female | 223 Participants | 113 Participants | 110 Participants |
| Sex: Female, Male Male | 234 Participants | 112 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 232 / 232 | 225 / 225 |
| serious Total, serious adverse events | 54 / 232 | 54 / 225 |
Outcome results
Primary
Number of Participants With Progression of Symptomatic Intracranial Stenosis
Blind reviewers classified the presence and severity of stenosis on middle cerebral arteries and basilar artery on magnetic resonance angiogram (MRA) into 5 grades; normal, mild, moderate, severe and occlusion. Progression was defined as worsening of stenosis by 1 or more grades on final MRA as compared with the baseline MRA. The progression of symptomatic stenosis is defined as 1 or more grade worsening of the stenosis on the symptomatic artery on MRA.
Time frame: 7 months after treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Participants With Progression of Symptomatic Intracranial Stenosis | 20 participants |
| Clopidogrel | Number of Participants With Progression of Symptomatic Intracranial Stenosis | 32 participants |
Secondary
Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI
number of patients with new ischemic lesions on FLAIR (Fluid attenuation inversion recovery) images of follow-up MRI, which were determined by slice to slice comparison with baseline MRI.
Time frame: 7 months after treatment
Population: this analysis included the patients who had performed follow-up FLAIR imaging
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI | 34 pariticipants |
| Clopidogrel | Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI | 23 pariticipants |
Secondary
Number of Participants With Overall Cardiovascular Events
including nonfatal stroke, nonfatal myocardial infarction and vascular death.
Time frame: upto 7 months after randomization
Population: this outcome analysis was done intention to treat method
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Participants With Overall Cardiovascular Events | 15 participants |
| Clopidogrel | Number of Participants With Overall Cardiovascular Events | 10 participants |
Secondary
Number of Participants With Stroke Events
including nonfatal ischemic stroke, nonfatal hemorrhagic stroke and fatal stroke
Time frame: upto 7 months after randomization
Population: this outcome analysis performed on the intention to treat (ITT) method
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Participants With Stroke Events | 11 participants |
| Clopidogrel | Number of Participants With Stroke Events | 7 participants |
Secondary
Number of Patients With Ipsilateral Ischemic Stroke Rate
ischemic stroke event which occured in the vascular territory of initial symptomatic stenosis
Time frame: upto 7 months after randomization
Population: this outcome analysis was done ITT method
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Patients With Ipsilateral Ischemic Stroke Rate | 9 participants |
| Clopidogrel | Number of Patients With Ipsilateral Ischemic Stroke Rate | 5 participants |
Secondary
Numbers of Fatal or Major Bleeding Complications
life-threatening or fatal bleeding was defined as any fatal bleeding event, a drop in hemoglobin of ≥ 50g/L, or significant hypotension with need for inotropic agents, symptomatic intracranial hemorrhage, or transfusion of ≥ 4 units of red-blood cells or equivalent amount of whole blood. Major bleeding was defined as significantly disabling bleedings, intraocular bleeding leading to significant visual loss, or bleeding requiring transfusion of ≤ 3 units of red-blood cells or equivalent amount of whole blood
Time frame: upto 7 months after randomization
Population: this outcome analysis was done ITT method
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Numbers of Fatal or Major Bleeding Complications | 2 events |
| Clopidogrel | Numbers of Fatal or Major Bleeding Complications | 6 events |