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

Brain Ischemia Clinical Trial

— PICASSO  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01013532
• Other study ID #: PICASSO
• Status: Active, not recruiting
• Phase: Phase 4
• First received: November 10, 2009
• Last updated: December 23, 2015
• Start date: June 2009
• Est. completion date: December 2016

Study information

• Verified date: December 2015
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1600
• Est. completion date: December 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Ischemia
• Cerebral Hemorrhage
• Hemorrhage
• Intracranial Hemorrhages
• Ischemia

Intervention

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

Device:
• ankle-brachial index (ABI)
measurement of ABI every years during follow up
• intima-medial thickness (IMT)
ultrasound measured IMT of both common carotid arteries
• new asymptomatic brain hemorrhage
asymptomatic macrobleedings or microbleedings on GRE images
• new ischemic lesions on follow-up FLAIR images
any new ischemic lesions

Locations

Country	Name	City	State
China	Pamela Youde Nethersole Eastern Hospital	Hong Kong	Hong Kong
China	Queen Elizabeth Hospital	Hong Kong	Hong Kong
China	United Christian Hospital	Hong Kong	Hong Kong
China	Prince of Wales Hospital	Shatin, NT	Hong Kong
Korea, Republic of	Korea University Ansan Hospital	Ansan	Gyeonggi-do
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang	Kyunggi
Korea, Republic of	Soonchunhyang University Bucheon Hospital	Bucheon	Gyeonggi-do
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Inje University Pusan Paik Hospital	Busan
Korea, Republic of	Kosin University Gospel Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Chang Won Fatima hospital	Changwon	Kyeongsangnam-do
Korea, Republic of	Samsung changwon Medical Center	Changwon	Gyeongsangnam-do
Korea, Republic of	Soonchunhyang University Cheonan Hospital	Cheonan	Chungcheongnam-do
Korea, Republic of	Chungbuk National University Hospital	Cheongju	Chungbuk
Korea, Republic of	Kangwon National University Hospital	Chuncheon	Kangwon-do
Korea, Republic of	Daegu Fatima Hospital	Daegu
Korea, Republic of	Keimyung University Dongsan Center	Daegu
Korea, Republic of	Eulji University Hospital	Daejon
Korea, Republic of	Deagu Catholic University Hospital	Deagu
Korea, Republic of	Dongsan Medical Center	Deagu
Korea, Republic of	Kyungpook National University Hospital	Deagu
Korea, Republic of	Yeungnam University Medical Center	Deagu
Korea, Republic of	Chungnam National University Hospital	Deajeon
Korea, Republic of	Deajeon St.Mary's Hospital, The Catholic University of Korea	Deajeon
Korea, Republic of	Dongguk University International Hospital	Goyang	Kyoungki-do
Korea, Republic of	Inje University Ilsan Paik Hospital	Goyang	Gyeonggi-do
Korea, Republic of	National Health Insurance Corporation Ilsan Hoapital	Goyang-si	Gyeonggi-do
Korea, Republic of	Hanyang University Guri Hospital	Guri	Gyeonggi-do
Korea, Republic of	Chonnam National University Hospital	Gwangju
Korea, Republic of	Chosun University Hospital	GwangJu
Korea, Republic of	Kwandong University College of Medicine Myongji Hospital	Gyeonggi-do	Goyang
Korea, Republic of	Wonkwang University Hospital	Iksan	Jeonbuk
Korea, Republic of	Gachon University Gil Hoapital	Incheon
Korea, Republic of	Inha University Hospital	Inchon
Korea, Republic of	Chonbuk National University Hospital	Jeonju-si	Jeonbuk
Korea, Republic of	Gyeongsang National University Hospital	Jinju	Gyengsangnam-do
Korea, Republic of	Wallace Memorial Baptist Hospital	Pusan
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam	Kyunggi
Korea, Republic of	Bundang Medical Center, CHA University	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chung-Ang University Medical Center	Seoul
Korea, Republic of	Eulji Hospital	Seoul
Korea, Republic of	Ewha Womans University Medical Center	Seoul
Korea, Republic of	Gangnam Severance Hospital	Seoul
Korea, Republic of	Hangang Sacred Heart Hospital	Seoul
Korea, Republic of	Hanyang University Medical Center	Seoul
Korea, Republic of	Inje University Sanggye Paik Hospital	Seoul
Korea, Republic of	Kangbuk Samsung Hospital	Seoul
Korea, Republic of	Kangdong Sacred Heart Hospital, Hallym University	Seoul
Korea, Republic of	Kangnam Sacred Heart Hospital, Hallym University College of Medicine	Seoul
Korea, Republic of	Konkuk Univ. Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Kyung Hee University Medical Center	Seoul
Korea, Republic of	National Medical Center	Seoul
Korea, Republic of	Seoul Medical Center	Seoul
Korea, Republic of	Seoul National University Borame Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul St.Mary's Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	Soonchunhyang University Hospital	Seoul
Korea, Republic of	St. Mary's Hospital	Seoul
Korea, Republic of	Ajou University Hospital	Suwon	Kyunggi
Korea, Republic of	Uijeongbu St. Mary's Hospital	Uijeongbu	Gyeonggi-do
Korea, Republic of	Ulsan University Hospital	Ulsan
Korea, Republic of	Wonju Christian Hospital	Wonju	Gangwon-do
Philippines	Manila Doctors Hospital	Manila
Philippines	University of Santo Tomas	Manila
Philippines	The Medical City	Pasig
Philippines	St. Luke's Medical Center	Quezon City

Sponsors (2)

Lead Sponsor	Collaborator
Asan Medical Center	Korea Otsuka Pharmaceutical Co., Ltd.

Countries where clinical trial is conducted

China,  Korea, Republic of,  Philippines, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence rate of major and non-major hemorrhagic event		time since randomization; follow-up period is 1.0 to 5.5 years
Other	Rate of asymptomatic hemorrhage in GRE (microhemorrhage or macrohemorrhage)		at final visit, follow-up MRI will be checked at the final visit
Other	Rate of new asymptomatic cerebral infarction lesion in FLAIR		at final visit, follow-up MRI will be checked at the final visit
Other	Change of ankle-brachial index		at final visit;follow-up period is 1.0 to 5.5 years
Other	The effect of the size of common carotid artery(CCA) including plaque on the occurrence of cardiovascular events		at final visit;follow-up period is 1.0 to 5.5 years
Other	Time to all deaths including vascular and non-vascular deaths		time since randomization; follow-up period is 1.0 to 5.5 years
Other	Incidence rate of dementia diagnosed after initiation of the trial		time since randomization; follow-up period is 1.0 to 5.5 years
Primary	Time to the first occurrence of cerebral hemorrhage		time since randomization; follow-up period is 1.0 to 5.5 years
Primary	Time to the first occurence of composite cardiovascular events		time since randomization; follow-up period is 1.0 to 5.5 years
Secondary	Time to the first occurrence of stroke		time since randomization; follow-up period is 1.0 to 5.5 years
Secondary	Time to the first occurrence of ischemic stroke		time since randomization; follow-up period is 1.0 to 5.5 years
Secondary	Time to the first occurence of myocardial infarction		time since randomization; follow-up period is 1.0 to 5.5 years
Secondary	Time to the first occurence of other designated vascular events		time since randomization; follow-up period is 1.0 to 5.5 years