PreventIon of CArdiovascular Events in iSchemic Stroke Patients With High Risk of Cerebral HemOrrhage "PICASSO"

Active, not recruiting

Phase 4 Results N/A

Trial Description

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.

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 cerebral hemorrhage findings(equal or more than 8mm) or multiple microbleeds on the GRE images.
- 1600 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 1600th 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.

Conditions

Interventions

  • Cilostazol (PletalĀ®)Drug
    Other Names: Claudiasil
    Intervention Desc: Cilostazol 100mg bid
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Cilostazol
    Description: cilostazol plus placebo of aspirin
  • Aspirin Drug
    Other Names: Aspirin at bedtime
    Intervention Desc: Aspirin 100mg qd
    ARM 1: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
    ARM 2: Kind: Experimental
    Label: Aspirin
    Description: aspirin plus placebo of cilostazol
  • Probucol Drug
    Other Names: Probucol is produced by Otsuka Pharmaceutical
    Intervention Desc: Probucol 250mg bid
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
  • Placebo of cilostazol Drug
    Intervention Desc: same shape and size of active cilostazol
    ARM 1: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
    ARM 2: Kind: Experimental
    Label: Aspirin
    Description: aspirin plus placebo of cilostazol
  • Placebo of aspirin Drug
    Intervention Desc: same size and shape of active aspirin 100mg
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Cilostazol
    Description: cilostazol plus placebo of aspirin
  • Ankle-brachial index (ABI) Device
    Intervention Desc: measurement of ABI every years during follow up
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
    ARM 3: Kind: Experimental
    Label: Cilostazol
    Description: cilostazol plus placebo of aspirin
    ARM 4: Kind: Experimental
    Label: Aspirin
    Description: aspirin plus placebo of cilostazol
  • Intima-medial thickness (IMT) Device
    Other Names: change of maximal IMT and mean IMT
    Intervention Desc: ultrasound measured IMT of both common carotid arteries
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
    ARM 3: Kind: Experimental
    Label: Cilostazol
    Description: cilostazol plus placebo of aspirin
    ARM 4: Kind: Experimental
    Label: Aspirin
    Description: aspirin plus placebo of cilostazol
  • New asymptomatic brain hemorrhage Device
    Intervention Desc: asymptomatic macrobleedings or microbleedings on GRE images
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
    ARM 3: Kind: Experimental
    Label: Cilostazol
    Description: cilostazol plus placebo of aspirin
    ARM 4: Kind: Experimental
    Label: Aspirin
    Description: aspirin plus placebo of cilostazol
  • New ischemic lesions on follow-up FLAIR images Device
    Intervention Desc: any new ischemic lesions
    ARM 1: Kind: Experimental
    Label: Cilostazol+ Probucol
    Description: 100mg cilostazol bid plus probucol plus placebo of aspirin
    ARM 2: Kind: Experimental
    Label: Aspirin + Probucol
    Description: aspirin plus placebo cilostazol plus probucol
    ARM 3: Kind: Experimental
    Label: Cilostazol
    Description: cilostazol plus placebo of aspirin
    ARM 4: Kind: Experimental
    Label: Aspirin
    Description: aspirin plus placebo of cilostazol

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Purpose: Prevention
  • Endpoint: Safety/Efficacy Study
  • Intervention: Factorial Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary time to first occurrence of cerebral hemorrhage time since randomization; follow-up period is 1.0 to 4.5 years Yes
Primary time to first occurrence of cardiovascular events time since randomization; follow-up period is 1.0 to 4.5 years No
Secondary Time to the first occurrence of stroke atime since randomization; follow-up period is 1.0 to 4.5 years No
Secondary Time to the first occurrence of ischemic stroke time since randomization; follow-up period is 1.0 to 4.5 years No
Secondary Time to the first occurrence of myocardial infarction time since randomization; follow-up period is 1.0 to 4.5 years No
Secondary Time to the first occurrence of other designated vascular events time since randomization; follow-up period is 1.0 to 4.5 years No
Secondary time to occurrence of major bleeding complications time since randomization; follow-up period is 1.0 to 4.5 years Yes
Secondary occurrence of new microbleedings or asymptomatic new hemorrhage on GRE image at final visit, follow-up MRI will be checked at the final visit No
Secondary new ischemic lesions on FLAIR images at final visit, follow-up MRI will be checked at the final visit No
Secondary change of Ankle-Brachial Index at final visit;follow-up period is 1.0 to 4.5 years No
Secondary change of intima-medial thickness at final visit;follow-up period is 1.0 to 4.5 years No
Secondary time to occurrence of any death time since randomization; follow-up period is 1.0 to 4.5 years No
Primary Time to the first occurrence of cerebral hemorrhage time since randomization; follow-up period is 1.0 to 5.5 years Yes
Primary Time to the first occurence of composite cardiovascular events time since randomization; follow-up period is 1.0 to 5.5 years No
Secondary Time to the first occurence of myocardial infarction time since randomization; follow-up period is 1.0 to 5.5 years No
Secondary Time to the first occurence of other designated vascular events time since randomization; follow-up period is 1.0 to 5.5 years No

Sponsors