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| Name | Class |
|---|---|
| Korea Otsuka Pharmaceutical Co., Ltd. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cilostazol+ Probucol | Experimental | 100mg cilostazol bid plus probucol plus placebo of aspirin |
|
| Aspirin + Probucol | Active Comparator | aspirin plus placebo cilostazol plus probucol |
|
| Cilostazol | Experimental | cilostazol plus placebo of aspirin |
|
| Aspirin | Active Comparator | aspirin plus placebo of cilostazol |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cilostazol | Drug | Cilostazol 100mg bid |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sun U. Kwon, MD, PhD | Departement of Neurology, Asan Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pamela Youde Nethersole Eastern Hospital | Hong Kong | Hong Kong | China | |||
| Queen Elizabeth Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36700520 | Derived | Cochrane A, Chen C, Stephen J, Ronning OM, Anderson CS, Hankey GJ, Al-Shahi Salman R. Antithrombotic treatment after stroke due to intracerebral haemorrhage. Cochrane Database Syst Rev. 2023 Jan 26;1(1):CD012144. doi: 10.1002/14651858.CD012144.pub3. | |
| 34779245 | Derived | Park JH, Lee J, Kwon SU, Sung Kwon H, Hwan Lee M, Kang DW. Elevated Pulse Pressure and Recurrent Hemorrhagic Stroke Risk in Stroke With Cerebral Microbleeds or Intracerebral Hemorrhage. J Am Heart Assoc. 2022 Feb;11(3):e022317. doi: 10.1161/JAHA.121.022317. Epub 2021 Nov 15. |
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| Type | Date | Date Unknown |
|---|---|---|
| Release | Dec 28, 2016 | |
| Reset | Feb 21, 2017 |
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| Probucol | Drug | Probucol 250mg bid |
|
|
| Aspirin | Drug | Aspirin 100mg qd |
|
| placebo of cilostazol | Drug | same shape and size of active cilostazol |
|
| placebo of aspirin | Drug | same size and shape of active aspirin 100mg |
|
| ankle-brachial index (ABI) | Device | measurement of ABI every years during follow up |
|
| intima-medial thickness (IMT) | Device | ultrasound measured IMT of both common carotid arteries |
|
|
| new asymptomatic brain hemorrhage | Device | asymptomatic macrobleedings or microbleedings on GRE images |
|
| new ischemic lesions on follow-up FLAIR images | Device | any new ischemic lesions |
|
| 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 |
| 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 |
| Hong Kong |
| Hong Kong |
| China |
| United Christian Hospital | Hong Kong | Hong Kong | China |
| Prince of Wales Hospital | Shatin, NT | Hong Kong | China |
| Manila Doctors Hospital | Manila | Philippines |
| University of Santo Tomas | Manila | Philippines |
| The Medical City | Pasig | Philippines |
| St. Luke's Medical Center | Quezon City | Philippines |
| Wallace Memorial Baptist Hospital | Busan | Busan | 609-728 | South Korea |
| Soonchunhyang University Cheonan Hospital | Cheonan | Chungcheongnam-do | 330-721 | South Korea |
| Keimyung University Dongsan Center | Daegu | Daegu | 700-712 | South Korea |
| Daegu Fatima Hospital | Daegu | Daegu | 701-600 | South Korea |
| Kangwon National University Hospital | Chuncheon | Gangwon-do | 200-947 | South Korea |
| Wonju Christian Hospital | Wŏnju | Gangwon-do | 220-701 | South Korea |
| Kwandong University College of Medicine Myongji Hospital | Gyeonggi-do | Goyang | 412-270 | South Korea |
| Gyeongsang National University Hospital | Jinju | Gyengsangnam-do | 660-702 | South Korea |
| Korea University Ansan Hospital | Ansan | Gyeonggi-do | 152-703 | South Korea |
| Soonchunhyang University Bucheon Hospital | Bucheon-si | Gyeonggi-do | 420-020 | South Korea |
| Inje University Ilsan Paik Hospital | Goyang-si | Gyeonggi-do | 411-706 | South Korea |
| National Health Insurance Corporation Ilsan Hoapital | Goyang-si | Gyeonggi-do | 411-719 | South Korea |
| Hanyang University Guri Hospital | Guri-si | Gyeonggi-do | 471-701 | South Korea |
| Bundang Medical Center, CHA University | Seongnam-si | Gyeonggi-do | 463-712 | South Korea |
| Uijeongbu St. Mary's Hospital | Uijeongbu-si | Gyeonggi-do | 480-821 | South Korea |
| Samsung changwon Medical Center | Changwon | Gyeongsangnam-do | 630-723 | South Korea |
| Wonkwang University Hospital | Iksan | Jeollabuk-do | 570-711 | South Korea |
| Chonbuk National University Hospital | Jeonju | Jeollabuk-do | 561-712 | South Korea |
| Chang Won Fatima hospital | Changwon | Kyeongsangnam-do | 641-560 | South Korea |
| Dongguk University International Hospital | Goyang | Kyoungki-do | 410-773 | South Korea |
| Hallym University Sacred Heart Hospital | Anyang | Kyunggi | 430-070 | South Korea |
| Seoul National University Bundang Hospital | Seongnam | Kyunggi | South Korea |
| Ajou University Hospital | Suwon | Kyunggi | South Korea |
| Chungbuk National University Hospital | Cheongju-si | North Chungcheong | 361-711 | South Korea |
| Kosin University Gospel Hospital | Busan | 602-702 | South Korea |
| Inje University Pusan Paik Hospital | Busan | 614-735 | South Korea |
| Pusan National University Hospital | Busan | 626-770 | South Korea |
| Dong-A University Hospital | Busan | South Korea |
| Eulji University Hospital | Daejeon | 302-799 | South Korea |
| Dongsan Medical Center | Deagu | 700-712 | South Korea |
| Kyungpook National University Hospital | Deagu | 700-721 | South Korea |
| Yeungnam University Medical Center | Deagu | 705-717 | South Korea |
| Deagu Catholic University Hospital | Deagu | 705-718 | South Korea |
| Chungnam National University Hospital | Deajeon | 301-721 | South Korea |
| Deajeon St.Mary's Hospital, The Catholic University of Korea | Deajeon | 303-723 | South Korea |
| Chosun University Hospital | Gwangju | 501-717 | South Korea |
| Chonnam National University Hospital | Gwangju | 501-757 | South Korea |
| Gachon University Gil Hoapital | Incheon | 405-760 | South Korea |
| Inha University Hospital | Inchon | 400-103 | South Korea |
| National Medical Center | Seoul | 100-799 | South Korea |
| Kangbuk Samsung Hospital | Seoul | 110-746 | South Korea |
| Severance Hospital | Seoul | 120-752 | South Korea |
| Kyung Hee University Medical Center | Seoul | 130-702 | South Korea |
| Hanyang University Medical Center | Seoul | 133-792 | South Korea |
| Kangdong Sacred Heart Hospital, Hallym University | Seoul | 134-701 | South Korea |
| Gangnam Severance Hospital | Seoul | 135-720 | South Korea |
| Seoul Medical Center | Seoul | 135-740 | South Korea |
| Korea University Anam Hospital | Seoul | 136-705 | South Korea |
| Seoul St.Mary's Hospital | Seoul | 137-701 | South Korea |
| Asan Medical Center | Seoul | 138-736 | South Korea |
| Inje University Sanggye Paik Hospital | Seoul | 139-707 | South Korea |
| Konkuk Univ. Hospital | Seoul | 143-729 | South Korea |
| St. Mary's Hospital | Seoul | 150-713 | South Korea |
| Hangang Sacred Heart Hospital | Seoul | 150-719 | South Korea |
| Kangnam Sacred Heart Hospital, Hallym University College of Medicine | Seoul | 150-950 | South Korea |
| Korea University Guro Hospital | Seoul | 152-703 | South Korea |
| Seoul National University Borame Hospital | Seoul | 156-707 | South Korea |
| Ewha Womans University Medical Center | Seoul | 158-710 | South Korea |
| Eulji Hospital | Seoul | 280-1 | South Korea |
| Chung-Ang University Medical Center | Seoul | South Korea |
| Seoul National University Hospital | Seoul | South Korea |
| Soonchunhyang University Hospital | Seoul | South Korea |
| Ulsan University Hospital | Ulsan | South Korea |
| 34155277 | Derived | Cho KH, Kwon SU, Lee JS, Yu S, Cho AH. Newly diagnosed diabetes has high risk for cardiovascular outcome in ischemic stroke patients. Sci Rep. 2021 Jun 21;11(1):12929. doi: 10.1038/s41598-021-92349-y. |
| 32664827 | Derived | Park HK, Lee JS, Kim BJ, Park JH, Kim YJ, Yu S, Hwang YH, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Kwon SU, Hong KS; PICASSO investigators. Cilostazol versus aspirin in ischemic stroke with cerebral microbleeds versus prior intracerebral hemorrhage. Int J Stroke. 2021 Dec;16(9):1019-1030. doi: 10.1177/1747493020941273. Epub 2020 Jul 14. |
| 32027796 | Derived | Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Kim HY, Kim EG, Kim SH, Cha JK, Park MS, Nam HS, Kang DW; PICASSO Investigators. Changes in High-Density Lipoprotein Cholesterol and Risks of Cardiovascular Events: A Post Hoc Analysis from the PICASSO Trial. J Stroke. 2020 Jan;22(1):108-118. doi: 10.5853/jos.2019.02551. Epub 2020 Jan 31. |
| 31856691 | Derived | Kim BJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LKS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Navarro JC, Kim HY, Kim EG, Kim S, Cha JK, Park MS, Nam HS, Kang DW; PICASSO Investigators. Cilostazol Versus Aspirin in Ischemic Stroke Patients With High-Risk Cerebral Hemorrhage: Subgroup Analysis of the PICASSO Trial. Stroke. 2020 Mar;51(3):931-937. doi: 10.1161/STROKEAHA.119.023855. Epub 2019 Dec 20. |
| 29778364 | Derived | Kim BJ, Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LKS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Navarro JC, Kang DW; PICASSO investigators. Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial. Lancet Neurol. 2018 Jun;17(6):509-518. doi: 10.1016/S1474-4422(18)30128-5. |
| 24957314 | Derived | Park TH, Lee JS, Park SS, Ko Y, Lee SJ, Lee KB, Lee J, Kang K, Park JM, Choi JC, Kim DE, Cho YJ, Kim JT, Kim DH, Cha JK, Han MK, Lee J, Oh MS, Yu KH, Lee BC, Bae HJ, Hong KS. Safety and efficacy of intravenous recombinant tissue plasminogen activator administered in the 3- to 4.5-hour window in Korea. J Stroke Cerebrovasc Dis. 2014 Aug;23(7):1805-12. doi: 10.1016/j.jstrokecerebrovasdis.2014.04.027. Epub 2014 Jun 21. |
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| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Dec 28, 2016 | Feb 21, 2017 |
| ID | Term |
|---|---|
| D002545 | Brain Ischemia |
| D020300 | Intracranial Hemorrhages |
| D000083242 | Ischemic Stroke |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D020521 | Stroke |
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| ID | Term |
|---|---|
| D000077407 | Cilostazol |
| D011341 | Probucol |
| D001241 | Aspirin |
| D055109 | Ankle Brachial Index |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D001795 | Blood Pressure Determination |
| D003935 | Diagnostic Techniques, Cardiovascular |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
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