Cerebral Infarction
Conditions
Keywords
Cerebral infarction, Cilostazol, Aspirin, Transcranial Doppler, Pulsatile Index
Brief summary
RATIONALE: * Elevation in pulsatility indices (PIs), measured by transcranial Doppler (TCD), has been postulated to reflect downstream increased vascular resistance caused by small-vessel disease (SVD). * Small arterial vessels are a significant determinant of vascular resistance and PIs are elevated when SVD is present in the intracranial circulation. * Cilostazol, a phosphodiesterase III inhibitor, has other non-antiplatelet effects, such as vasodilation and neuroprotective effect. It has been shown to be effective in the secondary prevention of stroke especially in the SVD and it may be related to the other non-antiplatelet effects of cilostazol. OBJECTIVES: * In this study, we aim to investigate whether cilostazol affects the changes of PIs in patients with acute lacunar infarction using serial TCDs. * Our hypothesis is that cilostazol has other non-antiplatelet effects such as vasodilation effect and may decrease the vascular resistance in patients with acute lacunar infarction. Hence, cilostazol will decrease the PIs in patients with acute lacunar infarction.
Detailed description
TREATMENTS: * Cilostazol is an agent inhibiting platelet aggregation. * A matching placebo of cilostazol is an inactive substance that looks similar to the active cilostazol tablet. TREATMENT PLAN: * There will be two treatment groups; one will receive cilostazol 200mg (100mg twice per day), the second matching placebo of cilostazol. * These study drugs will be administered on top of aspirin (100mg) systematically prescribed to such patients PRIMARY ENDPOINT: * The changes of PI between the baseline and 14 and 90 days follow-up study. STUDY EXECUTION: * Two hundred sixty patients, presenting with first ever lacunar infarction within 7 days after the onset of symptoms will be recruited within two years. * Patients will be followed up during the three months.
Interventions
DRUGAspirin
Asprin (100mg) plus placebo
DRUGcilostazol
Aspirin (100mg) plus cilostazol (200mg)
Sponsors
Korea Otsuka Pharmaceutical Co., Ltd.
Inje University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with first ever lacunar infarction within 7 days after the onset of symptoms * Age: more than 45 years of age
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) * 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. * Pregnant or lactating patients * Patients with hyperthyroidism or COPD * Patients with current anticoagulation or antiplatelet therapy * Patients with poor temporal window in transcranial Doppler
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | 14 days and 90 days from the baseline TCD study | The PI is designed to measure vascular resistance and characterizes the shape of the spectral waveform. For the study, the mean, systolic, and diastolic flow velocities were measured using TCD. Gosling's PI was determined as the difference between the peak systolic and end-diastolic velocities divided by the mean flow velocity in each artery.The changes of MCA and BA PIs at 14 and 90 days from the baseline TCD study was calculated for the study. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Patients With First Recurrent Stroke of Any Type | 90 days |
Countries
South Korea
Participant flow
Recruitment details
ECLIPse was designed as a multicenter, randomized, double-blind, placebo-controlled trial. Between November 2006 and October 2008, 203 patients were consecutively enrolled from eight tertiary-care hospitals.
Pre-assignment details
A total of 513 patients who had experienced their first classic lacunar syndromes were screened for study enrollment, of which 101 (19.7% of the screened population) refused to participate in the study. Seventy-four patients (14.4%) were not eligible for the trial, and 135 (26.3%) were excluded by the exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Asprin Plus Placebo Placebo twice a day on top of aspirin 100mg a day | 103 |
| Asprin Plus Cilostazol Cilostazol (100mg) twice a day on top of aspirin 100mg a day | 100 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 6 |
| Overall Study | Lost to Follow-up | 15 | 10 |
| Overall Study | Primary Outcome | 1 | 1 |
| Overall Study | Protocol Violation | 3 | 2 |
Baseline characteristics
| Characteristic | Asprin Plus Cilostazol | Asprin Plus Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 55 Participants | 56 Participants | 111 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 47 Participants | 92 Participants |
| Age Continuous | 64.63 years STANDARD_DEVIATION 9.07 | 65.48 years STANDARD_DEVIATION 9.92 | 65.06 years STANDARD_DEVIATION 9.5 |
| Region of Enrollment Korea, Republic of | 100 participants | 103 participants | 203 participants |
| Sex: Female, Male Female | 26 Participants | 25 Participants | 51 Participants |
| Sex: Female, Male Male | 74 Participants | 78 Participants | 152 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 103 | 0 / 100 |
| serious Total, serious adverse events | 0 / 83 | 0 / 81 |
Outcome results
Primary
The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study
The PI is designed to measure vascular resistance and characterizes the shape of the spectral waveform. For the study, the mean, systolic, and diastolic flow velocities were measured using TCD. Gosling's PI was determined as the difference between the peak systolic and end-diastolic velocities divided by the mean flow velocity in each artery.The changes of MCA and BA PIs at 14 and 90 days from the baseline TCD study was calculated for the study.
Time frame: 14 days and 90 days from the baseline TCD study
Population: Of the 203 patients included in the intention-to-treat analysis, 164 were included in the per-protocol analysis of the primary outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Asprin Plus Placebo | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Right MCA (14 days) | 0.07 ratio | Standard Deviation 0.13 |
| Asprin Plus Placebo | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Right MCA (90 days) | 0.09 ratio | Standard Deviation 0.13 |
| Asprin Plus Placebo | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Left MCA (14 days) | 0.08 ratio | Standard Deviation 0.13 |
| Asprin Plus Placebo | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Left MCA (90 days) | 0.07 ratio | Standard Deviation 0.13 |
| Asprin Plus Placebo | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in BA (14 days) | 0.09 ratio | Standard Deviation 0.14 |
| Asprin Plus Placebo | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in BA (90 days) | 0.1 ratio | Standard Deviation 0.18 |
| Asprin Plus Cilostazol | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in BA (14 days) | 0.09 ratio | Standard Deviation 0.14 |
| Asprin Plus Cilostazol | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Right MCA (14 days) | 0.08 ratio | Standard Deviation 0.13 |
| Asprin Plus Cilostazol | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Left MCA (90 days) | 0.13 ratio | Standard Deviation 0.13 |
| Asprin Plus Cilostazol | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Right MCA (90 days) | 0.14 ratio | Standard Deviation 0.13 |
| Asprin Plus Cilostazol | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in BA (90 days) | 0.18 ratio | Standard Deviation 0.16 |
| Asprin Plus Cilostazol | The Changes of Middle Cerebral Artery (MCA) and Basilar Artery (BA) Pulsatility Index (PI) at 14 and 90 Days From the Baseline Transcranial Doppler (TCD) Study | Changes of PI in Left MCA (14 days) | 0.1 ratio | Standard Deviation 0.14 |
Comparison: A linear mixed model for a repeated measures covariance pattern model with unstructured covariances within subjects was used. Two fixed effects were included: 1 between-subjects treatment effect (group: cilostazol, control) and 1 within-subject time effect (time: baseline, 14 days, 90 days). A possible difference in treatment across 14- and 90-day follow-up was analyzed by time x treatment interactions.p-value: <0.05Mixed Models Analysis
Comparison: To determine between-group differences of changes in the PIs at 14 and 90 days from the baseline study.p-value: <0.05t-test, 2 sided
Secondary
Number of Patients With First Recurrent Stroke of Any Type
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asprin Plus Placebo | Number of Patients With First Recurrent Stroke of Any Type | 1 participants |
| Asprin Plus Cilostazol | Number of Patients With First Recurrent Stroke of Any Type | 1 participants |
p-value: <0.05Chi-squared