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

December 23, 2015 updated by: Sun U. Kwon, Asan Medical Center

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

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 Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

1600

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Hong Kong
      • Hong Kong, Hong Kong, China
        • Pamela Youde Nethersole Eastern Hospital
      • Hong Kong, Hong Kong, China
        • Queen Elizabeth Hospital
      • Hong Kong, Hong Kong, China
        • United Christian Hospital
      • Shatin, NT, Hong Kong, China
        • Prince of Wales Hospital
  • Korea, Republic of
      • Busan, Korea, Republic of, 602-702
        • Kosin University Gospel Hospital
      • Busan, Korea, Republic of
        • Dong-A University Hospital
      • Busan, Korea, Republic of, 614-735
        • Inje University Pusan Paik Hospital
      • Busan, Korea, Republic of, 626-770
        • Pusan National University Hospital
      • Daegu, Korea, Republic of, 700-712
        • Keimyung University Dongsan Center
      • Daegu, Korea, Republic of, 701-600
        • Daegu fatima hospital
      • Daejon, Korea, Republic of, 302-799
        • Eulji University Hospital
      • Deagu, Korea, Republic of, 700-712
        • Dongsan Medical Center
      • Deagu, Korea, Republic of, 700-721
        • Kyungpook National University Hospital
      • Deagu, Korea, Republic of, 705-717
        • Yeungnam University Medical Center
      • Deagu, Korea, Republic of, 705-718
        • Deagu Catholic University Hospital
      • Deajeon, Korea, Republic of, 301-721
        • Chungnam National University Hospital
      • Deajeon, Korea, Republic of, 303-723
        • Deajeon St.Mary's Hospital, The Catholic University of Korea
      • GwangJu, Korea, Republic of, 501-717
        • Chosun university hospital
      • Gwangju, Korea, Republic of, 501-757
        • Chonnam National University Hospital
      • Incheon, Korea, Republic of, 405-760
        • Gachon University Gil Hoapital
      • Inchon, Korea, Republic of, 400-103
        • Inha University Hospital
      • Pusan, Korea, Republic of, 609-728
        • Wallace Memorial Baptist Hospital
      • Seoul, Korea, Republic of
        • Seoul National University Hospital
      • Seoul, Korea, Republic of, 138-736
        • Asan Medical Center
      • Seoul, Korea, Republic of, 135-720
        • Gangnam Severance Hospital
      • Seoul, Korea, Republic of, 152-703
        • Korea University Guro Hospital
      • Seoul, Korea, Republic of, 120-752
        • Severance Hospital
      • Seoul, Korea, Republic of, 136-705
        • Korea University Anam Hospital
      • Seoul, Korea, Republic of, 158-710
        • Ewha womans university medical center
      • Seoul, Korea, Republic of, 134-701
        • Kangdong Sacred Heart Hospital, Hallym University
      • Seoul, Korea, Republic of, 280-1
        • Eulji Hospital
      • Seoul, Korea, Republic of, 110-746
        • Kangbuk Samsung Hospital
      • Seoul, Korea, Republic of
        • Soonchunhyang University Hospital
      • Seoul, Korea, Republic of, 137-701
        • Seoul St.Mary's Hospital
      • Seoul, Korea, Republic of, 133-792
        • Hanyang University Medical Center
      • Seoul, Korea, Republic of, 135-740
        • Seoul Medical Center
      • Seoul, Korea, Republic of, 130-702
        • Kyung Hee University Medical Center
      • Seoul, Korea, Republic of, 100-799
        • National Medical Center
      • Seoul, Korea, Republic of, 139-707
        • Inje University Sanggye Paik Hospital
      • Seoul, Korea, Republic of, 143-729
        • Konkuk Univ. Hospital
      • Seoul, Korea, Republic of, 150-713
        • St. Mary's Hospital
      • Seoul, Korea, Republic of, 150-719
        • Hangang Sacred Heart Hospital
      • Seoul, Korea, Republic of, 150-950
        • Kangnam Sacred Heart Hospital, Hallym University College of Medicine
      • Seoul, Korea, Republic of, 156-707
        • Seoul National University Borame Hospital
      • Seoul, Korea, Republic of
        • Chung-Ang University Medical Center
      • Ulsan, Korea, Republic of
        • Ulsan University Hospital
    • Chungbuk
      • Cheongju, Chungbuk, Korea, Republic of, 361-711
        • Chungbuk National University Hospital
    • Chungcheongnam-do
      • Cheonan, Chungcheongnam-do, Korea, Republic of, 330-721
        • Soonchunhyang University Cheonan Hospital
    • Gangwon-do
      • Wonju, Gangwon-do, Korea, Republic of, 220-701
        • Wonju Christian Hospital
    • Goyang
      • Gyeonggi-do, Goyang, Korea, Republic of, 412-270
        • Kwandong University college of Medicine Myongji Hospital
    • Gyengsangnam-do
      • Jinju, Gyengsangnam-do, Korea, Republic of, 660-702
        • Gyeongsang National University Hospital
    • Gyeonggi-do
      • Ansan, Gyeonggi-do, Korea, Republic of, 152-703
        • Korea University Ansan Hospital
      • Bucheon, Gyeonggi-do, Korea, Republic of, 420-020
        • SoonChunHyang University Bucheon Hospital
      • Goyang, Gyeonggi-do, Korea, Republic of, 411-706
        • Inje University Ilsan Paik Hospital
      • Goyang-si, Gyeonggi-do, Korea, Republic of, 411-719
        • National Health Insurance Corporation Ilsan Hoapital
      • Guri, Gyeonggi-do, Korea, Republic of, 471-701
        • Hanyang University Guri Hospital
      • Seongnam-si, Gyeonggi-do, Korea, Republic of, 463-712
        • Bundang Medical Center, CHA University
      • Uijeongbu, Gyeonggi-do, Korea, Republic of, 480-821
        • Uijeongbu St. Mary's Hospital
    • Gyeongsangnam-do
      • Changwon, Gyeongsangnam-do, Korea, Republic of, 630-723
        • Samsung Changwon Medical Center
    • Jeonbuk
      • Iksan, Jeonbuk, Korea, Republic of, 570-711
        • Wonkwang University Hospital
      • Jeonju-si, Jeonbuk, Korea, Republic of, 561-712
        • Chonbuk National University Hospital
    • Kangwon-do
      • Chuncheon, Kangwon-do, Korea, Republic of, 200-947
        • Kangwon National University Hospital
    • Kyeongsangnam-do
      • Changwon, Kyeongsangnam-do, Korea, Republic of, 641-560
        • Chang Won Fatima hospital
    • Kyoungki-do
      • Goyang, Kyoungki-do, Korea, Republic of, 410-773
        • DongGuk University International Hospital
    • Kyunggi
      • Anyang, Kyunggi, Korea, Republic of, 430-070
        • Hallym University Sacred Heart Hospital
      • Seongnam, Kyunggi, Korea, Republic of
        • Seoul National University Bundang Hospital
      • Suwon, Kyunggi, Korea, Republic of
        • Ajou University Hospital
  • Philippines
      • Manila, Philippines
        • Manila Doctors Hospital
      • Manila, Philippines
        • University of Santo Tomas
      • Pasig, Philippines
        • The Medical City
      • Quezon City, Philippines
        • St. Luke's Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cilostazol+ Probucol
100mg cilostazol bid plus probucol plus placebo of aspirin
Drug: Cilostazol
Cilostazol 100mg bid
Other Names:
  • Pletaal produced by Korea Otsuka Pharmaceutical company
Drug: Probucol
Probucol 250mg bid
Other Names:
  • 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 Names:
  • 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 Names:
  • Probucol is produced by Otsuka Pharmaceutical
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 Names:
  • 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
Drug: Aspirin
Aspirin 100mg qd
Drug: placebo of cilostazol
same shape and size of active cilostazol
Experimental: Cilostazol
cilostazol plus placebo of aspirin
Drug: Cilostazol
Cilostazol 100mg bid
Other Names:
  • 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 Names:
  • 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
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 Names:
  • 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
Drug: Aspirin
Aspirin 100mg qd
Drug: placebo of cilostazol
same shape and size of active cilostazol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Time to the first occurrence of cerebral hemorrhage
Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years
time since randomization; follow-up period is 1.0 to 5.5 years
Time to the first occurence of composite cardiovascular events
Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years
time since randomization; follow-up period is 1.0 to 5.5 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Time to the first occurrence of stroke
Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years
time since randomization; follow-up period is 1.0 to 5.5 years
Time to the first occurrence of ischemic stroke
Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years
time since randomization; follow-up period is 1.0 to 5.5 years
Time to the first occurence of myocardial infarction
Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years
time since randomization; follow-up period is 1.0 to 5.5 years
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
time since randomization; follow-up period is 1.0 to 5.5 years

Other Outcome Measures

Outcome Measure
Time Frame
Incidence rate of major and non-major hemorrhagic event
Time Frame: time since randomization; follow-up period is 1.0 to 5.5 years
time since randomization; follow-up period is 1.0 to 5.5 years
Rate of asymptomatic hemorrhage in GRE (microhemorrhage or macrohemorrhage)
Time Frame: at final visit, follow-up MRI will be checked at the final visit
at final visit, follow-up MRI will be checked at the final visit
Rate of new asymptomatic cerebral infarction lesion in FLAIR
Time Frame: at final visit, follow-up MRI will be checked at the final visit
at final visit, follow-up MRI will be checked at the final visit
Change of ankle-brachial index
Time Frame: at final visit;follow-up period is 1.0 to 5.5 years
at final visit;follow-up period is 1.0 to 5.5 years
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
at final visit;follow-up period is 1.0 to 5.5 years
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
time since randomization; follow-up period is 1.0 to 5.5 years
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
time since randomization; follow-up period is 1.0 to 5.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Asan Medical Center

Collaborators

Korea Otsuka Pharmaceutical Co., Ltd.

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2009

Primary Completion (Anticipated)

September 1, 2016

Study Completion (Anticipated)

December 1, 2016

Study Registration Dates

First Submitted

November 10, 2009

First Submitted That Met QC Criteria

November 12, 2009

First Posted (Estimate)

November 13, 2009

Study Record Updates

Last Update Posted (Estimate)

December 24, 2015

Last Update Submitted That Met QC Criteria

December 23, 2015

Last Verified

December 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PICASSO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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