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

Sponsor

Asan Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT01013532

Collaborator

Korea Otsuka Pharmaceutical Co., Ltd. (Industry)

1,600

Enrollment

Locations

Arms

Duration (Months)

22.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	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

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 Design

Study Type:

Interventional

Anticipated Enrollment :

1600 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, 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

Study Start Date :

Jun 1, 2009

Anticipated Primary Completion Date :

Sep 1, 2016

Anticipated Study Completion Date :

Dec 1, 2016

Arms and Interventions

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 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 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
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	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 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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Time to the first occurrence of stroke [time since randomization; follow-up period is 1.0 to 5.5 years]
Time to the first occurrence of ischemic stroke [time since randomization; follow-up period is 1.0 to 5.5 years]
Time to the first occurence of myocardial infarction [time since randomization; follow-up period is 1.0 to 5.5 years]
Time to the first occurence of other designated vascular events [time since randomization; follow-up period is 1.0 to 5.5 years]

Other Outcome Measures

Incidence rate of major and non-major hemorrhagic event [time since randomization; follow-up period is 1.0 to 5.5 years]
Rate of asymptomatic hemorrhage in GRE (microhemorrhage or macrohemorrhage) [at final visit, follow-up MRI will be checked at the final visit]
Rate of new asymptomatic cerebral infarction lesion in FLAIR [at final visit, follow-up MRI will be checked at the final visit]
Change of ankle-brachial index [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 [at final visit;follow-up period is 1.0 to 5.5 years]
Time to all deaths including vascular and non-vascular deaths [time since randomization; follow-up period is 1.0 to 5.5 years]
Incidence rate of dementia diagnosed after initiation of the trial [time since randomization; follow-up period is 1.0 to 5.5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Pamela Youde Nethersole Eastern Hospital	Hong Kong	Hong Kong	China
2	Queen Elizabeth Hospital	Hong Kong	Hong Kong	China
3	United Christian Hospital	Hong Kong	Hong Kong	China
4	Prince of Wales Hospital	Shatin, NT	Hong Kong	China
5	Chungbuk National University Hospital	Cheongju	Chungbuk	Korea, Republic of	361-711
6	Soonchunhyang University Cheonan Hospital	Cheonan	Chungcheongnam-do	Korea, Republic of	330-721
7	Wonju Christian Hospital	Wonju	Gangwon-do	Korea, Republic of	220-701
8	Kwandong University College of Medicine Myongji Hospital	Gyeonggi-do	Goyang	Korea, Republic of	412-270
9	Gyeongsang National University Hospital	Jinju	Gyengsangnam-do	Korea, Republic of	660-702
10	Korea University Ansan Hospital	Ansan	Gyeonggi-do	Korea, Republic of	152-703
11	Soonchunhyang University Bucheon Hospital	Bucheon	Gyeonggi-do	Korea, Republic of	420-020
12	National Health Insurance Corporation Ilsan Hoapital	Goyang-si	Gyeonggi-do	Korea, Republic of	411-719
13	Inje University Ilsan Paik Hospital	Goyang	Gyeonggi-do	Korea, Republic of	411-706
14	Hanyang University Guri Hospital	Guri	Gyeonggi-do	Korea, Republic of	471-701
15	Bundang Medical Center, CHA University	Seongnam-si	Gyeonggi-do	Korea, Republic of	463-712
16	Uijeongbu St. Mary's Hospital	Uijeongbu	Gyeonggi-do	Korea, Republic of	480-821
17	Samsung changwon Medical Center	Changwon	Gyeongsangnam-do	Korea, Republic of	630-723
18	Wonkwang University Hospital	Iksan	Jeonbuk	Korea, Republic of	570-711
19	Chonbuk National University Hospital	Jeonju-si	Jeonbuk	Korea, Republic of	561-712
20	Kangwon National University Hospital	Chuncheon	Kangwon-do	Korea, Republic of	200-947
21	Chang Won Fatima hospital	Changwon	Kyeongsangnam-do	Korea, Republic of	641-560
22	Dongguk University International Hospital	Goyang	Kyoungki-do	Korea, Republic of	410-773
23	Hallym University Sacred Heart Hospital	Anyang	Kyunggi	Korea, Republic of	430-070
24	Seoul National University Bundang Hospital	Seongnam	Kyunggi	Korea, Republic of
25	Ajou University Hospital	Suwon	Kyunggi	Korea, Republic of
26	Kosin University Gospel Hospital	Busan		Korea, Republic of	602-702
27	Inje University Pusan Paik Hospital	Busan		Korea, Republic of	614-735
28	Pusan National University Hospital	Busan		Korea, Republic of	626-770
29	Dong-A University Hospital	Busan		Korea, Republic of
30	Keimyung University Dongsan Center	Daegu		Korea, Republic of	700-712
31	Daegu Fatima Hospital	Daegu		Korea, Republic of	701-600
32	Eulji University Hospital	Daejon		Korea, Republic of	302-799
33	Dongsan Medical Center	Deagu		Korea, Republic of	700-712
34	Kyungpook National University Hospital	Deagu		Korea, Republic of	700-721
35	Yeungnam University Medical Center	Deagu		Korea, Republic of	705-717
36	Deagu Catholic University Hospital	Deagu		Korea, Republic of	705-718
37	Chungnam National University Hospital	Deajeon		Korea, Republic of	301-721
38	Deajeon St.Mary's Hospital, The Catholic University of Korea	Deajeon		Korea, Republic of	303-723
39	Chosun University Hospital	GwangJu		Korea, Republic of	501-717
40	Chonnam National University Hospital	Gwangju		Korea, Republic of	501-757
41	Gachon University Gil Hoapital	Incheon		Korea, Republic of	405-760
42	Inha University Hospital	Inchon		Korea, Republic of	400-103
43	Wallace Memorial Baptist Hospital	Pusan		Korea, Republic of	609-728
44	National Medical Center	Seoul		Korea, Republic of	100-799
45	Kangbuk Samsung Hospital	Seoul		Korea, Republic of	110-746
46	Severance Hospital	Seoul		Korea, Republic of	120-752
47	Kyung Hee University Medical Center	Seoul		Korea, Republic of	130-702
48	Hanyang University Medical Center	Seoul		Korea, Republic of	133-792
49	Kangdong Sacred Heart Hospital, Hallym University	Seoul		Korea, Republic of	134-701
50	Gangnam Severance Hospital	Seoul		Korea, Republic of	135-720
51	Seoul Medical Center	Seoul		Korea, Republic of	135-740
52	Korea University Anam Hospital	Seoul		Korea, Republic of	136-705
53	Seoul St.Mary's Hospital	Seoul		Korea, Republic of	137-701
54	Asan Medical Center	Seoul		Korea, Republic of	138-736
55	Inje University Sanggye Paik Hospital	Seoul		Korea, Republic of	139-707
56	Konkuk Univ. Hospital	Seoul		Korea, Republic of	143-729
57	St. Mary's Hospital	Seoul		Korea, Republic of	150-713
58	Hangang Sacred Heart Hospital	Seoul		Korea, Republic of	150-719
59	Kangnam Sacred Heart Hospital, Hallym University College of Medicine	Seoul		Korea, Republic of	150-950
60	Korea University Guro Hospital	Seoul		Korea, Republic of	152-703
61	Seoul National University Borame Hospital	Seoul		Korea, Republic of	156-707
62	Ewha Womans University Medical Center	Seoul		Korea, Republic of	158-710
63	Eulji Hospital	Seoul		Korea, Republic of	280-1
64	Chung-Ang University Medical Center	Seoul		Korea, Republic of
65	Seoul National University Hospital	Seoul		Korea, Republic of
66	Soonchunhyang University Hospital	Seoul		Korea, Republic of
67	Ulsan University Hospital	Ulsan		Korea, Republic of
68	Manila Doctors Hospital	Manila		Philippines
69	University of Santo Tomas	Manila		Philippines
70	The Medical City	Pasig		Philippines
71	St. Luke's Medical Center	Quezon City		Philippines