Cerebral Infarction
Conditions
Brief summary
The purpose of this study is to investigate the efficacy of cilostazol in preventing recurrence of cerebral infarction and the safety of long-term administration of the drug (100 mg, twice daily) in patients with cerebral infarction (excluding cardiogenic cerebral embolism) in a multi-center, double-blind, parallel-group comparison with aspirin (81 mg, once daily).
Interventions
DRUGCilostazol
oral tablet, 100 mg twice a day and placebo of aspirin once a day, 1 to 5years
DRUGAspirin
oral tablet, placebo of cilostazol twice a day and 81 mg once a day, 1 to 5 years
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with stable medical conditions for 182 days (26 weeks) after occurrence of cerebral infarction 2. Patients in whom the infarct-related foci was detected by X-ray CT scan or MRI 3. Patients aged 20 to 80 years (inclusive) at time of consent 4. Patients with none of the following cardiac diseases that may be associated with cardiogenic cerebral embolism: mitral stenosis, prosthetic heart valve, endocarditis, myocardial infarction within 6 weeks after occurrence, ventricular aneurysm, endocardial thrombosis, mitral valve prolapse (patients less than 45 years of age in whom no other cause was identified), atrial fibrillation, sick sinus syndrome, idiopathic cardiomyopathy, and patent foramen ovale 5. Patients without asymptomatic cerebral infarction 6. Patients who have neither undergone nor are scheduled to undergo percutaneous transluminal angioplasty or revascularization for the treatment of cerebral infarction 7. Patients without severe disturbances/impairments following occurrence of cerebral
Exclusion criteria
1. Patients with hemorrhage or bleeding tendency (hemophilia, capillary fragility, intracranial hemorrhage, hemorrhage in the digestive tract, hemorrhage in the urinary tract, hemoptysis, and hemorrhage in the vitreous body) 2. Pregnant, possibly pregnant, or nursing women 3. Patients with ischemic heart failure 4. Patients with peptic ulcer 5. Patients with severer blood disorders 6. Patients with severe hepatic or renal 7. Patients with malignant neoplasm or patients who have received any therapy for malignant neoplasm within 5 years prior to entering the study 8. Patients with a history of hypersensitivity to salicylic acid formulations or ingredients of cilostazol tablets 9. Patients with aspirin asthma (asthma attacks induced by nonsteroidal antiinflammatory analgesic agents) or a history of aspirin asthma 10. Patients who are being treated with ticlopidine hydrochloride 11. Patients who are participating in another study for an investigational drug 12. Patients who are otherwise judged inappropriate for inclusion in the study by the investigators
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Numbers of Patients With First Occurence of Stroke | From start of treatment to end of follow-up period ( follow-up periods : 29 months [Standard Deviation 16, range 1-59 months]) | The endpoint in this measure is a composite endpoint of the first recurrence of cerebral infarction, or occurrence of cerebral haemorrhage or subarachnoid haemorrhage. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With First Recurrence of Cerebral Infarction | From start of treatment to end of follow-up period (mean follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months]) | — |
| Number of Patients With First Occurrence of Ischaemic Cerebrovascular Disease | From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months]) | The endpoint in this measure is a composite endpoint of the first recurrence of cerebral infarction or the first occurrence of transient ischaemic attack. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints. |
| Number of Deaths From Any Cause | From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months]) | Number of deaths from any cause. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints. |
| Number of Patients With First Occurrence of a Composite Endpoint of Stroke, Haemorrhagic Events, or Cardiovascular Events | From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months]) | The endpoint in this measure is a composite endpoint of the first recurrence of cerebral infarction, or occurrence of cerebral haemorrhage, subarachnoid haemorrhage, transient ischaemic attack, angina pectris, myocardial infarction, heart failure, or haemorrhage requiring hospital admission. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With First Occurrence of Haemorrhagic Event | From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months]) | The endpoint in this measure is a composite endpoint of the first occurrence of cerebral haemorrhage, subarachnoid haemorrhage or haemorrhage requiring hospital admission. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints. |
Countries
Japan
Participant flow
Recruitment details
Patients with non-cardioembolic ischemic stroke have been recruited at 278 study sites in Japan between December, 2003, and October, 2006.
Pre-assignment details
No screening period
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol cilostazol, oral tablet, 100 mg cilostazol | 1,337 |
| Aspirin Aspirin, oral tablet, 81 mg aspirin | 1,335 |
| Total | 2,672 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 268 | 166 |
| Overall Study | Not Classified | 111 | 112 |
| Overall Study | Physician Decision | 23 | 22 |
| Overall Study | Withdrawal by Subject | 73 | 56 |
Baseline characteristics
| Characteristic | Aspirin | Cilostazol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 650 Participants | 656 Participants | 1306 Participants |
| Age, Categorical Between 18 and 65 years | 685 Participants | 681 Participants | 1366 Participants |
| Age Continuous | 63.4 years STANDARD_DEVIATION 9 | 63.5 years STANDARD_DEVIATION 9.2 | 63.4 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment Japan | 1335 participants | 1337 participants | 2672 participants |
| Sex: Female, Male Female | 378 Participants | 378 Participants | 756 Participants |
| Sex: Female, Male Male | 957 Participants | 959 Participants | 1916 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,267 / 1,337 | 1,260 / 1,335 |
| serious Total, serious adverse events | 372 / 1,337 | 433 / 1,335 |
Outcome results
Primary
Numbers of Patients With First Occurence of Stroke
The endpoint in this measure is a composite endpoint of the first recurrence of cerebral infarction, or occurrence of cerebral haemorrhage or subarachnoid haemorrhage. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints.
Time frame: From start of treatment to end of follow-up period ( follow-up periods : 29 months [Standard Deviation 16, range 1-59 months])
Population: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Numbers of Patients With First Occurence of Stroke | 82 participants |
| Aspirin | Numbers of Patients With First Occurence of Stroke | 119 participants |
Comparison: Statistical Analysis 1 for Number of Patients With First Occurrence of Strokep-value: 0.035795% CI: [0.564, 0.981]Log Rank
Secondary
Number of Deaths From Any Cause
Number of deaths from any cause. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints.
Time frame: From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months])
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Deaths From Any Cause | 13 participants |
| Aspirin | Number of Deaths From Any Cause | 13 participants |
Comparison: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.p-value: 0.8695% CI: [0.497, 2.313]Log Rank
Secondary
Number of Patients With First Occurrence of a Composite Endpoint of Stroke, Haemorrhagic Events, or Cardiovascular Events
The endpoint in this measure is a composite endpoint of the first recurrence of cerebral infarction, or occurrence of cerebral haemorrhage, subarachnoid haemorrhage, transient ischaemic attack, angina pectris, myocardial infarction, heart failure, or haemorrhage requiring hospital admission. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints.
Time frame: From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months])
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Patients With First Occurrence of a Composite Endpoint of Stroke, Haemorrhagic Events, or Cardiovascular Events | 138 participants |
| Aspirin | Number of Patients With First Occurrence of a Composite Endpoint of Stroke, Haemorrhagic Events, or Cardiovascular Events | 186 participants |
Comparison: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.p-value: 0.043795% CI: [0.643, 0.994]Log Rank
Secondary
Number of Patients With First Occurrence of Ischaemic Cerebrovascular Disease
The endpoint in this measure is a composite endpoint of the first recurrence of cerebral infarction or the first occurrence of transient ischaemic attack. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints.
Time frame: From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months])
Population: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Patients With First Occurrence of Ischaemic Cerebrovascular Disease | 86 participants |
| Aspirin | Number of Patients With First Occurrence of Ischaemic Cerebrovascular Disease | 103 participants |
Comparison: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.p-value: 0.458295% CI: [0.675, 1.194]Log Rank
Secondary
Number of Patients With First Recurrence of Cerebral Infarction
Time frame: From start of treatment to end of follow-up period (mean follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months])
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Patients With First Recurrence of Cerebral Infarction | 72 participants |
| Aspirin | Number of Patients With First Recurrence of Cerebral Infarction | 88 participants |
Comparison: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.p-value: 0.418995% CI: [0.645, 1.2]Log Rank
Other Pre-specified
Number of Patients With First Occurrence of Haemorrhagic Event
The endpoint in this measure is a composite endpoint of the first occurrence of cerebral haemorrhage, subarachnoid haemorrhage or haemorrhage requiring hospital admission. The evaluation committee, whose members were unaware of patients' treatment assignment, adjudicated all trial endpoints.
Time frame: From start of treatment to end of follow-up period ( follow-up periods : 29 months [STANDARD DEVIATION 16, range 1-59 months])
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Number of Patients With First Occurrence of Haemorrhagic Event | 23 participants |
| Aspirin | Number of Patients With First Occurrence of Haemorrhagic Event | 57 participants |
Comparison: Analyses were done using the full analysis set (FAS) of patients, as predetermined in the protocol. The full analysis set excluded patients who failed to satisfy inclusion criteria and those who violated exclusion criteria.p-value: 0.000495% CI: [0.296, 0.711]Log Rank