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

NCT01013532 | Unknown Phase 4 DMC

• 1 other identifier: PICASSO
• Study Type: interventional
• Target: 1,600
• Locations: 3 countries
• Sites: 71

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.

Conditions

Brain Ischemia; Intracranial Hemorrhages

Keywords

Ischemic Stroke; Intracranial Hemorrhage; Cilostazol; Probucol

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• 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 Outcomes (7)

• 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

Study Arms (4)

Cilostazol+ Probucol

EXPERIMENTAL

100mg cilostazol bid plus probucol plus placebo of aspirin

Drug: Cilostazol; Drug: Probucol; 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

Aspirin + Probucol

ACTIVE COMPARATOR

aspirin plus placebo cilostazol plus probucol

Drug: Probucol; Drug: Aspirin; Drug: placebo of cilostazol; Device: ankle-brachial index (ABI); Device: intima-medial thickness (IMT); Device: new asymptomatic brain hemorrhage; Device: new ischemic lesions on follow-up FLAIR images

Cilostazol

EXPERIMENTAL

cilostazol plus placebo of aspirin

Drug: 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

Aspirin

ACTIVE COMPARATOR

aspirin plus placebo of cilostazol

Drug: Aspirin; Drug: placebo of cilostazol; Device: ankle-brachial index (ABI); Device: intima-medial thickness (IMT); Device: new asymptomatic brain hemorrhage; Device: new ischemic lesions on follow-up FLAIR images

Interventions

Cilostazol DRUG

Cilostazol 100mg bid

Also known as: Pletaal produced by Korea Otsuka Pharmaceutical company

Cilostazol; Cilostazol+ Probucol

Probucol DRUG

Probucol 250mg bid

Also known as: Probucol is produced by Otsuka Pharmaceutical

Aspirin + Probucol; Cilostazol+ Probucol

Aspirin DRUG

Aspirin 100mg qd

Aspirin; Aspirin + Probucol

placebo of cilostazol DRUG

same shape and size of active cilostazol

Aspirin; Aspirin + Probucol

placebo of aspirin DRUG

same size and shape of active aspirin 100mg

Cilostazol; Cilostazol+ Probucol

ankle-brachial index (ABI) DEVICE

measurement of ABI every years during follow up

Aspirin; Aspirin + Probucol; Cilostazol; Cilostazol+ Probucol

intima-medial thickness (IMT) DEVICE

ultrasound measured IMT of both common carotid arteries

Also known as: change of maximal IMT and mean IMT

Aspirin; Aspirin + Probucol; Cilostazol; Cilostazol+ Probucol

new asymptomatic brain hemorrhage DEVICE

asymptomatic macrobleedings or microbleedings on GRE images

Aspirin; Aspirin + Probucol; Cilostazol; Cilostazol+ Probucol

new ischemic lesions on follow-up FLAIR images DEVICE

any new ischemic lesions

Aspirin; Aspirin + Probucol; Cilostazol; Cilostazol+ Probucol

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Asan Medical Center: lead
• Korea Otsuka Pharmaceutical Co., Ltd.: collaborator

Study Sites (71)

Pamela Youde Nethersole Eastern Hospital

Hong Kong, Hong Kong, China

Location

Queen Elizabeth Hospital

Hong Kong, Hong Kong, China

Location

United Christian Hospital

Hong Kong, Hong Kong, China

Location

Prince of Wales Hospital

Shatin, NT, Hong Kong, China

Location

Manila Doctors Hospital

Manila, Philippines

Location

University of Santo Tomas

Manila, Philippines

Location

The Medical City

Pasig, Philippines

Location

St. Luke's Medical Center

Quezon City, Philippines

Location

Wallace Memorial Baptist Hospital

Busan, Busan, 609-728, South Korea

Location

Soonchunhyang University Cheonan Hospital

Cheonan, Chungcheongnam-do, 330-721, South Korea

Location

Keimyung University Dongsan Center

Daegu, Daegu, 700-712, South Korea

Location

Daegu Fatima Hospital

Daegu, Daegu, 701-600, South Korea

Location

Kangwon National University Hospital

Chuncheon, Gangwon-do, 200-947, South Korea

Location

Wonju Christian Hospital

Wŏnju, Gangwon-do, 220-701, South Korea

Location

Kwandong University College of Medicine Myongji Hospital

Gyeonggi-do, Goyang, 412-270, South Korea

Location

Gyeongsang National University Hospital

Jinju, Gyengsangnam-do, 660-702, South Korea

Location

Korea University Ansan Hospital

Ansan, Gyeonggi-do, 152-703, South Korea

Location

Soonchunhyang University Bucheon Hospital

Bucheon-si, Gyeonggi-do, 420-020, South Korea

Location

Inje University Ilsan Paik Hospital

Goyang-si, Gyeonggi-do, 411-706, South Korea

Location

National Health Insurance Corporation Ilsan Hoapital

Goyang-si, Gyeonggi-do, 411-719, South Korea

Location

Hanyang University Guri Hospital

Guri-si, Gyeonggi-do, 471-701, South Korea

Location

Bundang Medical Center, CHA University

Seongnam-si, Gyeonggi-do, 463-712, South Korea

Location

Uijeongbu St. Mary's Hospital

Uijeongbu-si, Gyeonggi-do, 480-821, South Korea

Location

Samsung changwon Medical Center

Changwon, Gyeongsangnam-do, 630-723, South Korea

Location

Wonkwang University Hospital

Iksan, Jeollabuk-do, 570-711, South Korea

Location

Chonbuk National University Hospital

Jeonju, Jeollabuk-do, 561-712, South Korea

Location

Chang Won Fatima hospital

Changwon, Kyeongsangnam-do, 641-560, South Korea

Location

Dongguk University International Hospital

Goyang, Kyoungki-do, 410-773, South Korea

Location

Hallym University Sacred Heart Hospital

Anyang, Kyunggi, 430-070, South Korea

Location

Seoul National University Bundang Hospital

Seongnam, Kyunggi, South Korea

Location

Ajou University Hospital

Suwon, Kyunggi, South Korea

Location

Chungbuk National University Hospital

Cheongju-si, North Chungcheong, 361-711, South Korea

Location

Kosin University Gospel Hospital

Busan, 602-702, South Korea

Location

Inje University Pusan Paik Hospital

Busan, 614-735, South Korea

Location

Pusan National University Hospital

Busan, 626-770, South Korea

Location

Dong-A University Hospital

Busan, South Korea

Location

Eulji University Hospital

Daejeon, 302-799, South Korea

Location

Dongsan Medical Center

Deagu, 700-712, South Korea

Location

Kyungpook National University Hospital

Deagu, 700-721, South Korea

Location

Yeungnam University Medical Center

Deagu, 705-717, South Korea

Location

Deagu Catholic University Hospital

Deagu, 705-718, South Korea

Location

Chungnam National University Hospital

Deajeon, 301-721, South Korea

Location

Deajeon St.Mary's Hospital, The Catholic University of Korea

Deajeon, 303-723, South Korea

Location

Chosun University Hospital

Gwangju, 501-717, South Korea

Location

Chonnam National University Hospital

Gwangju, 501-757, South Korea

Location

Gachon University Gil Hoapital

Incheon, 405-760, South Korea

Location

Inha University Hospital

Inchon, 400-103, South Korea

Location

National Medical Center

Seoul, 100-799, South Korea

Location

Kangbuk Samsung Hospital

Seoul, 110-746, South Korea

Location

Severance Hospital

Seoul, 120-752, South Korea

Location

Kyung Hee University Medical Center

Seoul, 130-702, South Korea

Location

Hanyang University Medical Center

Seoul, 133-792, South Korea

Location

Kangdong Sacred Heart Hospital, Hallym University

Seoul, 134-701, South Korea

Location

Gangnam Severance Hospital

Seoul, 135-720, South Korea

Location

Seoul Medical Center

Seoul, 135-740, South Korea

Location

Korea University Anam Hospital

Seoul, 136-705, South Korea

Location

Seoul St.Mary's Hospital

Seoul, 137-701, South Korea

Location

Asan Medical Center

Seoul, 138-736, South Korea

Location

Inje University Sanggye Paik Hospital

Seoul, 139-707, South Korea

Location

Konkuk Univ. Hospital

Seoul, 143-729, South Korea

Location

St. Mary's Hospital

Seoul, 150-713, South Korea

Location

Hangang Sacred Heart Hospital

Seoul, 150-719, South Korea

Location

Kangnam Sacred Heart Hospital, Hallym University College of Medicine

Seoul, 150-950, South Korea

Location

Korea University Guro Hospital

Seoul, 152-703, South Korea

Location

Seoul National University Borame Hospital

Seoul, 156-707, South Korea

Location

Ewha Womans University Medical Center

Seoul, 158-710, South Korea

Location

Eulji Hospital

Seoul, 280-1, South Korea

Location

Chung-Ang University Medical Center

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

Soonchunhyang University Hospital

Seoul, South Korea

Location

Ulsan University Hospital

Ulsan, South Korea

Location

Related Publications (8)

• 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.

  PMID: 36700520 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.

  PMID: 34779245 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.

  PMID: 34155277 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.

  PMID: 32664827 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.

  PMID: 32027796 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.

  PMID: 31856691 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.

  PMID: 29778364 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.

  PMID: 24957314 DERIVED

MeSH Terms

Conditions

Brain Ischemia; Intracranial Hemorrhages; Ischemic Stroke

Interventions

Cilostazol; Probucol; Aspirin; Ankle Brachial Index

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Stroke

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Salicylates; Hydroxybenzoates; Blood Pressure Determination; Diagnostic Techniques, Cardiovascular; Diagnostic Techniques and Procedures; Diagnosis

Study Officials

• Sun U. Kwon, MD, PhD

  Departement of Neurology, Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 10, 2009
• First Posted: November 13, 2009
• Study Start: June 1, 2009
• Primary Completion: September 1, 2016
• Study Completion: December 1, 2016
• Last Updated: December 24, 2015

Record last verified: 2015-12

Locations

CN (4); PH (4); KR (63)