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”

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.

Study Type: Interventional

Study Design: Allocation: Randomized, Control: Active Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Study Primary Completion Date: December 2013

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.

Intervention(s) in this Clinical Trial

• Drug: Cilostazol
  • Cilostazol 100mg bid
• Drug: Probucol
  • Probucol 250mg bid
• Drug: Aspirin
  • Aspirin 100mg qd
• Drug: placebo of cilostazol
  • same shape and size of active cilostazol
• 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
• 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

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Cilostazol+ Probucol
  • 100mg cilostazol bid plus probucol plus placebo of aspirin
• Active Comparator: Aspirin + Probucol
  • aspirin plus placebo cilostazol plus probucol
• Experimental: Cilostazol
  • cilostazol plus placebo of aspirin
• Active Comparator: Aspirin
  • aspirin plus placebo of cilostazol

Primary Measures

• time to first occurrence of cerebral hemorrhage
  • Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years
    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
    Safety Issue?: No

Secondary Measures

• Time to the first occurrence of stroke
  • Time Frame: atime since randomization; follow-up period is 1.0 to 4.5 years
    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
    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
    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
    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
    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
    Safety Issue?: No
• new ischemic lesions on FLAIR images
  • Time Frame: at final visit, follow-up MRI will be checked at the final visit
    Safety Issue?: No
• change of Ankle-Brachial Index
  • Time Frame: at final visit;follow-up period is 1.0 to 4.5 years
    Safety Issue?: No
• change of intima-medial thickness
  • Time Frame: at final visit;follow-up period is 1.0 to 4.5 years
    Safety Issue?: No
• time to occurrence of any death
  • Time Frame: time since randomization; follow-up period is 1.0 to 4.5 years
    Safety Issue?: 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 20 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Asan Medical Center

Overall Clinical Trial Officials and Contacts

Sun U. Kwon, MD, PhD Principal Investigator Departement of Neurology, Asan Medical Center  

Overall Contact: Sun U. Kwon, MD, PhD 82-2-3010-3960 sukwon@amc.seoul.kr

Information obtained from ClinicalTrials.gov on March 18, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01013532

Study ID Number: PICASSO

ClinicalTrials.gov Identifier: NCT01013532

Health Authority: Korea: Food and Drug Administration

Web-CRF