PreventIon of CArdiovascular Events in iSchemic Stroke Patients With High Risk of Cerebral HemOrrhage (PICASSO)
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Purpose
Through this study, the investigators are to prove that Cilostazol effectively prevent cardiovascular events in ischemic stroke patients with high risk of cerebral hemorrhage, along with no significant increase in the risk of occurrence of hemorrhagic side effects.
The primary hypothesis of this study is; Cilostazol alone or with probucol will reduce the risk of cerebral hemorrhage without increase of cardiovascular events compared to aspirin in the ischemic stroke patients with symptomatic or asymptomatic old cerebral hemorrhage.
This study will prove the superiority of cilostazol on the prevention of cerebral hemorrhagic events without increasing the cardiovascular events against aspirin and the superiority of probucol on the prevention of overall cardiovascular events.
| Condition | Intervention | Phase |
|---|---|---|
|
Brain Ischemia Intracranial Hemorrhages |
Drug: Cilostazol Drug: Probucol Drug: Aspirin Drug: placebo of cilostazol Drug: placebo of aspirin Device: ankle-brachial index (ABI) Device: intima-medial thickness (IMT) Device: new asymptomatic brain hemorrhage Device: new ischemic lesions on follow-up FLAIR images |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Factorial Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention |
| Official Title: | Double Blind Placebo Controlled Multicenter Trial for Prevention of Cardiovascular Diseases in the Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage With Cilostazol and Probucol |
- time to first occurrence of cerebral hemorrhage [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: Yes ]
- time to first occurrence of cardiovascular events [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- Time to the first occurrence of stroke [ Time Frame: atime since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- Time to the first occurrence of ischemic stroke [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- Time to the first occurrence of myocardial infarction [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- Time to the first occurrence of other designated vascular events [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- time to occurrence of major bleeding complications [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: Yes ]
- occurrence of new microbleedings or asymptomatic new hemorrhage on GRE image [ Time Frame: at final visit, follow-up MRI will be checked at the final visit ] [ Designated as safety issue: No ]
- new ischemic lesions on FLAIR images [ Time Frame: at final visit, follow-up MRI will be checked at the final visit ] [ Designated as safety issue: No ]
- change of Ankle-Brachial Index [ Time Frame: at final visit;follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- change of intima-medial thickness [ Time Frame: at final visit;follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
- time to occurrence of any death [ Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 1592 |
| Study Start Date: | June 2009 |
| Estimated Study Completion Date: | August 2014 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Cilostazol+ Probucol
100mg cilostazol bid plus probucol plus placebo of aspirin
|
Drug: Cilostazol
Cilostazol 100mg bid
Other Name: Pletaal produced by Korea Otsuka Pharmaceutical company
Drug: Probucol
Probucol 250mg bid
Other Name: Probucol is produced by Otsuka Pharmaceutical
Drug: placebo of aspirin
same size and shape of active aspirin 100mg
Device: ankle-brachial index (ABI)
measurement of ABI every years during follow up
Device: intima-medial thickness (IMT)
ultrasound measured IMT of both common carotid arteries
Other Name: change of maximal IMT and mean IMT
Device: new asymptomatic brain hemorrhage
asymptomatic macrobleedings or microbleedings on GRE images
Device: new ischemic lesions on follow-up FLAIR images
any new ischemic lesions
|
|
Active Comparator: Aspirin + Probucol
aspirin plus placebo cilostazol plus probucol
|
Drug: Probucol
Probucol 250mg bid
Other Name: Probucol is produced by Otsuka Pharmaceutical
Drug: Aspirin
Aspirin 100mg qd
Drug: placebo of cilostazol
same shape and size of active cilostazol
Device: ankle-brachial index (ABI)
measurement of ABI every years during follow up
Device: intima-medial thickness (IMT)
ultrasound measured IMT of both common carotid arteries
Other Name: change of maximal IMT and mean IMT
Device: new asymptomatic brain hemorrhage
asymptomatic macrobleedings or microbleedings on GRE images
Device: new ischemic lesions on follow-up FLAIR images
any new ischemic lesions
|
|
Experimental: Cilostazol
cilostazol plus placebo of aspirin
|
Drug: Cilostazol
Cilostazol 100mg bid
Other Name: Pletaal produced by Korea Otsuka Pharmaceutical company
Drug: placebo of aspirin
same size and shape of active aspirin 100mg
Device: ankle-brachial index (ABI)
measurement of ABI every years during follow up
Device: intima-medial thickness (IMT)
ultrasound measured IMT of both common carotid arteries
Other Name: change of maximal IMT and mean IMT
Device: new asymptomatic brain hemorrhage
asymptomatic macrobleedings or microbleedings on GRE images
Device: new ischemic lesions on follow-up FLAIR images
any new ischemic lesions
|
|
Active Comparator: Aspirin
aspirin plus placebo of cilostazol
|
Drug: Aspirin
Aspirin 100mg qd
Drug: placebo of cilostazol
same shape and size of active cilostazol
Device: ankle-brachial index (ABI)
measurement of ABI every years during follow up
Device: intima-medial thickness (IMT)
ultrasound measured IMT of both common carotid arteries
Other Name: change of maximal IMT and mean IMT
Device: new asymptomatic brain hemorrhage
asymptomatic macrobleedings or microbleedings on GRE images
Device: new ischemic lesions on follow-up FLAIR images
any new ischemic lesions
|
Detailed Description:
It has been generally accepted that 'old age' and 'hypertension' may be risk factors not only for cerebral infarction but also for cerebral hemorrhage. Usually 40 to 60 percent of recurrent strokes after cerebral hemorrhage cases are cerebral infarction; and 5 to 10 percent of recurrent stroke after cerebral infarction cases are cerebral hemorrhage.
Consequently, for the reasons described above, hemorrhagic side effects including cerebral hemorrhage have been a great concern, in the usage of antiplatelet agent or anticoagulant for the secondary prevention in the patients with cerebral infarction.
It is reported that the occurrence of cerebral hemorrhage tends to increase in cases of accompanying lacunar infarction which occurs more frequently in Asians than in Westerners, or periventricular ischemic change which increasingly occurs with ageing. Accordingly, the point is that the occurrence of cerebral hemorrhage should be primarily considered in the treatment of cerebral infarction, along with the phenomenon of an ageing population both in Asian countries including Korea.
Nevertheless, so far there has been no clinical research regarding secondary prevention of stroke, particularly considering the risk of occurrence of hemorrhage in cerebral infarction cases. However, according to a recent study, when phosphodiesterase inhibitors including Cilostazol are used independently, or in combination with aspirin, secondary prevention can be improved without increasing the occurrence of hemorrhagic side effects.
Considering this, if it is proved that the agent, Cilostazol, could decrease the risk of occurrence of stoke, along with no significant increase in the risk of occurrence of hemorrhagic side effects, by selecting a patent group with a high risk of cerebral hemorrhage, the agent (Cilostazol) may be recognized as an unique antiplatelet agent applicable to old-aged patient with cerebral infarction who have a certain risk of cerebral hemorrhage.
- High risk of cerebral hemorrhage is defined as presence of history of cerebral hemorrhage with appropriate neuroimage findings or presence of asymptomatic old intraparenchymal hemorrhage (more than 10mm) on the GRE images.
- 1592 ischemic stroke patients with high risk of cerebral hemorrhage will be recruited and they are randomized into four groups (cilostazol plus probucol, aspirin plus probucol, cilostazol and aspirin) by 2X2 factorial design.
- IMT and ABI will be measured every year during follow-up period and the results will be compared with the baseline data. The change of IMT and ABI will be analyzed with the occurrence of cardiovascular events.
- The study will finish at least 1 year after the recruit of 1592th patients. Until the finish, all patients will continuously take study medications and visit every 3months at the study site.
- Brain MRI including FLAIR and GRE will be done at the final visits.
Eligibility| Ages Eligible for Study: | 20 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Clinical diagnosis of ischemic stroke within 120 days
- Adult aged 20 years or older
- High risk of hemorrhagic stroke (history of intracranial hemorrhage or imaging evidence of previous intracranial hemorrhage)
- Informed consent
Exclusion Criteria:
- Clinical diagnosis of myocardial infarction or coronary intervention within 4 weeks
- Bleeding tendency
- Pregnant or breast-feeding woman
- Hemorrhagic stroke within 6 months
- Patient who was taking antithrombotic medication other than aspirin and does not agree to change the previous medication
- Severe cardiovascular disease such as cardiomyopathy or congestive heart failure
- Life expectancy less than one year
- Contraindication to long term aspirin use
- Enrolled in other clinical trial within 30 days
Contacts and Locations| Contact: Sun U. Kwon, MD, PhD | 82-2-3010-3960 | sukwon@amc.seoul.kr |
Show 73 Study Locations| Principal Investigator: | Sun U. Kwon, MD, PhD | Departement of Neurology, Asan Medical Center |
More Information
Additional Information:
No publications provided
| Responsible Party: | Sun U. Kwon/ Principal Investigator of PICASSO, Asan Medical Center |
| ClinicalTrials.gov Identifier: | NCT01013532 History of Changes |
| Other Study ID Numbers: | PICASSO |
| Study First Received: | November 10, 2009 |
| Last Updated: | June 14, 2012 |
| Health Authority: | Korea: Food and Drug Administration |
Keywords provided by Asan Medical Center:
|
Ischemic Stroke Intracranial Hemorrhage Cilostazol Probucol |
Additional relevant MeSH terms:
|
Cardiovascular Diseases Brain Ischemia Hemorrhage Ischemia Stroke Intracranial Hemorrhages Cerebral Hemorrhage Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Vascular Diseases Pathologic Processes Aspirin Cilostazol |
Probucol Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Pharmacologic Actions Anti-Inflammatory Agents Therapeutic Uses Antirheumatic Agents Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Cardiovascular Agents |
ClinicalTrials.gov processed this record on May 21, 2013