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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Korea Otsuka Pharmaceutical Co.,Ltd.
Information provided by (Responsible Party):
Sun U. Kwon, Asan Medical Center
ClinicalTrials.gov Identifier:
NCT01013532
First received: November 10, 2009
Last updated: October 8, 2014
Last verified: November 2009
  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: A Multicenter, Double Blind, Factorial Design, Phase IV Trial to Compare the Efficacy and Safety of Cilostazol Long-term Treatment With Aspirin in Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage for the Prevention of Cerebral Hemorrhage and Cardiovascular Events and to Compare the Preventive Effect of Probucol in the Same Patient Group With Non-drug User Group for the Prevention of Cardiovascular Events

Resource links provided by NLM:


Further study details as provided by Asan Medical Center:

Primary Outcome Measures:
  • Time to the first occurrence of cerebral hemorrhage [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: Yes ]
  • Time to the first occurence of composite cardiovascular events [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to the first occurrence of stroke [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 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 5.5 years ] [ Designated as safety issue: No ]
  • Time to the first occurence of myocardial infarction [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: No ]
  • Time to the first occurence of other designated vascular events [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Incidence rate of major and non-major hemorrhagic event [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: Yes ]
  • Rate of asymptomatic hemorrhage in GRE (microhemorrhage or macrohemorrhage) [ Time Frame: at final visit, follow-up MRI will be checked at the final visit ] [ Designated as safety issue: Yes ]
  • Rate of new asymptomatic cerebral infarction lesion in FLAIR [ 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 5.5 years ] [ Designated as safety issue: No ]
  • The effect of the size of common carotid artery(CCA) including plaque on the occurrence of cardiovascular events [ Time Frame: at final visit;follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: No ]
  • Time to all deaths including vascular and non-vascular deaths [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: No ]
  • Incidence rate of dementia diagnosed after initiation of the trial [ Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 1600
Study Start Date: June 2009
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: August 2015 (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 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.
  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with transient ischemic attack (TIA) or ischemic stroke within 180 days prior to screening - 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01013532

  Show 71 Study Locations
Sponsors and Collaborators
Asan Medical Center
Korea Otsuka Pharmaceutical Co.,Ltd.
Investigators
Principal Investigator: Sun U. Kwon, MD, PhD Departement of Neurology, Asan Medical Center
  More Information

Additional Information:
No publications provided by Asan Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sun U. Kwon, Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT01013532     History of Changes
Other Study ID Numbers: PICASSO
Study First Received: November 10, 2009
Last Updated: October 8, 2014
Health Authority: Korea: Food and Drug Administration

Keywords provided by Asan Medical Center:
Ischemic Stroke
Intracranial Hemorrhage
Cilostazol
Probucol

Additional relevant MeSH terms:
Brain Ischemia
Cerebral Hemorrhage
Hemorrhage
Intracranial Hemorrhages
Brain Diseases
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Nervous System Diseases
Pathologic Processes
Vascular Diseases
Aspirin
Cilostazol
Probucol
Analgesics
Analgesics, Non-Narcotic
Anti-Asthmatic Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Anticholesteremic Agents
Antimetabolites
Antioxidants
Antipyretics
Antirheumatic Agents
Autonomic Agents
Bronchodilator Agents
Cardiovascular Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 21, 2014