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Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II (TOSS-2)

Primary Purpose

Cerebral Infarction, Atherosclerosis

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
clopidogrel
Cilostazol
Sponsored by
Asan Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cerebral Infarction focused on measuring Infarction, Cerebral, cilostazol, stenosis, atherosclerosis, clopidogrel

Eligibility Criteria

35 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Cerebral infarction within 2 weeks from the onset or TIA with corresponding acute ischemic brain lesions on MRI within 2 weeks from the onset Age: more than 35 years of age Patient with significant focal stenosis in the M1 segment of middle cerebral artery (MCA) or basilar artery (BA) with acute ischemic lesions on magnetic resonance imaging (MRI) within the vascular territory of the stenosed artery. Exclusion Criteria: Patients with any contraindications to the treatment with antiplatelet therapy Patients with potential cardiac embolic source; prosthetic valve, atrial fibrillation, atrial flutter, left atrial/atrial appendage thrombus, sick sinus syndrome, left ventricular thrombus, dilated cardiomyopathy, akinetic or hypokinetic left ventricular segment, atrial myxoma, Infective endocarditis, mitral valve stenosis or prolapse, mitral annuls calcification, left atrial turbulence, nonbacterial endocarditis, congestive heart failure, recent myocardial infarction (within 4 weeks) Patients with more than 50% stenosis in the parent artery of symptomatic stenosis Bleeding diathesis Chronic liver disease (ALT > 100 or AST > 100) or chronic renal disease (creatinine > 3.0mg/dl) Anemia (hemoglobin < 10mg/dl) or thrombocytopenia (platelet count less than 100,000/mm3) Nonatherosclerotic vasculopathy; patients with clinical characteristics suggesting arterial dissection, moyamoya disease, Takayasu's arteritis, radiation associated angiopathy, and other vasculitis. Severe stroke: NIH stroke scale : more than 16 Pregnant or lactating patients Chronic user of NSAIDs Thrombolytic therapy for the symptomatic stenosis Symptomatic stenosis scheduled for angioplasty Patients with pacemaker or any other contraindications to MRI

Sites / Locations

  • Prince of Wales Hospital
  • Queen Mary Hospital
  • Konkuk Univ. Hospital
  • Inje University Ilsan Paik Hospital
  • Dongguk University International Hospital
  • Hallym University Sacred Heart Hospital
  • Inha University Hospital
  • Seoul National University Bundang Hospital
  • Seoul National University Hospital
  • Kangdong Sacred Heart Hospital, Hallym University
  • Samsung Medical Center
  • Asan Medical Center
  • Soonchunhyang University Hospital
  • Seoul National University Boramae Hospital
  • Eulji Hospital
  • Philippine General Hospital
  • University of Santo Tomas Hospital
  • Ramathibodi Hospital
  • Siriraj Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

cilostazol

Clopidogrel

Arm Description

cilostazol 100mg bid plus placebo of clopidogrel

clopidogrel 75mg qd and matching placebo of cilostazol

Outcomes

Primary Outcome Measures

Number of Participants With Progression of Symptomatic Intracranial Stenosis
Blind reviewers classified the presence and severity of stenosis on middle cerebral arteries and basilar artery on magnetic resonance angiogram (MRA) into 5 grades; normal, mild, moderate, severe and occlusion. Progression was defined as worsening of stenosis by 1 or more grades on final MRA as compared with the baseline MRA. The progression of symptomatic stenosis is defined as 1 or more grade worsening of the stenosis on the symptomatic artery on MRA.

Secondary Outcome Measures

Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI
number of patients with new ischemic lesions on FLAIR (Fluid attenuation inversion recovery) images of follow-up MRI, which were determined by slice to slice comparison with baseline MRI.
Number of Participants With Stroke Events
including nonfatal ischemic stroke, nonfatal hemorrhagic stroke and fatal stroke
Number of Participants With Overall Cardiovascular Events
including nonfatal stroke, nonfatal myocardial infarction and vascular death.
Number of Patients With Ipsilateral Ischemic Stroke Rate
ischemic stroke event which occured in the vascular territory of initial symptomatic stenosis
Numbers of Fatal or Major Bleeding Complications
life-threatening or fatal bleeding was defined as any fatal bleeding event, a drop in hemoglobin of ≥ 50g/L, or significant hypotension with need for inotropic agents, symptomatic intracranial hemorrhage, or transfusion of ≥ 4 units of red-blood cells or equivalent amount of whole blood. Major bleeding was defined as significantly disabling bleedings, intraocular bleeding leading to significant visual loss, or bleeding requiring transfusion of ≤ 3 units of red-blood cells or equivalent amount of whole blood

Full Information

First Posted
August 11, 2005
Last Updated
January 4, 2010
Sponsor
Asan Medical Center
Collaborators
Korea Otsuka International Asia Arab
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1. Study Identification

Unique Protocol Identification Number
NCT00130039
Brief Title
Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II
Acronym
TOSS-2
Official Title
Trial for Efficacy and Safety of Cilostazol on the Progression of Symptomatic Intracranial Stenosis Comparing Clopidogrel
Study Type
Interventional

2. Study Status

Record Verification Date
November 2009
Overall Recruitment Status
Completed
Study Start Date
August 2005 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
January 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Asan Medical Center
Collaborators
Korea Otsuka International Asia Arab

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will recruit 480 acute stroke patients with symptomatic intracranial stenosis (M1 segment of Middle cerebral artery (MCA) or basilar artery). They will be randomly assigned into cilostazol group or clopidogrel group. Every patients will take 100mg of aspirin a day additionally. The primary outcome variable of this study is Progression rate of symptomatic intracranial stenosis on magnetic resonance angiogram (MRA).
Detailed Description
[Goal] To Reveal the Effect and Safety of Cilostazol Compared with Clopidogrel on the Prevention of the Progression of Symptomatic Intracranial Arterial Stenosis. [Trial Design] Double-Blind, Active-Controlled, Randomized, Multicenter Trial [Participants] Acute ischemic stroke patients with symptomatic intracranial arterial stenosis [Methods] Double-Blind, Active-Controlled, Randomized, Multicenter Trial Investigational product (Double Dummy Method): Cilostazol 200mg (100mg twice per day) versus clopidogrel 75mg Concomitant medication: Aspirin 100 (75-150) mg per day Medication Duration: 7 months [Outcome Variables] Primary Outcome Variable: Progression rate of symptomatic intracranial arterial stenosis Secondary outcome variables: The occurrence of new MRI (magnetic resonance image) lesion on follow-up MRI Stroke events Overall cardiovascular events: stroke, acute coronary syndrome, vascular death Ipsilateral ischemic stroke rate Fatal or major bleeding complications

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Infarction, Atherosclerosis
Keywords
Infarction, Cerebral, cilostazol, stenosis, atherosclerosis, clopidogrel

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
457 (Actual)

8. Arms, Groups, and Interventions

Arm Title
cilostazol
Arm Type
Experimental
Arm Description
cilostazol 100mg bid plus placebo of clopidogrel
Arm Title
Clopidogrel
Arm Type
Active Comparator
Arm Description
clopidogrel 75mg qd and matching placebo of cilostazol
Intervention Type
Drug
Intervention Name(s)
clopidogrel
Other Intervention Name(s)
Plavix, produced by Sanofi-Aventis.
Intervention Description
Clopidogrel 75mg once a day plus placebo of cilostazol twice a day
Intervention Type
Drug
Intervention Name(s)
Cilostazol
Other Intervention Name(s)
cilostazol produced by Korea Otsuka Pharmaceutical
Intervention Description
Cilostazol 100mg twice a day plus placebo of clopidogrel once a day
Primary Outcome Measure Information:
Title
Number of Participants With Progression of Symptomatic Intracranial Stenosis
Description
Blind reviewers classified the presence and severity of stenosis on middle cerebral arteries and basilar artery on magnetic resonance angiogram (MRA) into 5 grades; normal, mild, moderate, severe and occlusion. Progression was defined as worsening of stenosis by 1 or more grades on final MRA as compared with the baseline MRA. The progression of symptomatic stenosis is defined as 1 or more grade worsening of the stenosis on the symptomatic artery on MRA.
Time Frame
7 months after treatment
Secondary Outcome Measure Information:
Title
Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI
Description
number of patients with new ischemic lesions on FLAIR (Fluid attenuation inversion recovery) images of follow-up MRI, which were determined by slice to slice comparison with baseline MRI.
Time Frame
7 months after treatment
Title
Number of Participants With Stroke Events
Description
including nonfatal ischemic stroke, nonfatal hemorrhagic stroke and fatal stroke
Time Frame
upto 7 months after randomization
Title
Number of Participants With Overall Cardiovascular Events
Description
including nonfatal stroke, nonfatal myocardial infarction and vascular death.
Time Frame
upto 7 months after randomization
Title
Number of Patients With Ipsilateral Ischemic Stroke Rate
Description
ischemic stroke event which occured in the vascular territory of initial symptomatic stenosis
Time Frame
upto 7 months after randomization
Title
Numbers of Fatal or Major Bleeding Complications
Description
life-threatening or fatal bleeding was defined as any fatal bleeding event, a drop in hemoglobin of ≥ 50g/L, or significant hypotension with need for inotropic agents, symptomatic intracranial hemorrhage, or transfusion of ≥ 4 units of red-blood cells or equivalent amount of whole blood. Major bleeding was defined as significantly disabling bleedings, intraocular bleeding leading to significant visual loss, or bleeding requiring transfusion of ≤ 3 units of red-blood cells or equivalent amount of whole blood
Time Frame
upto 7 months after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Cerebral infarction within 2 weeks from the onset or TIA with corresponding acute ischemic brain lesions on MRI within 2 weeks from the onset Age: more than 35 years of age Patient with significant focal stenosis in the M1 segment of middle cerebral artery (MCA) or basilar artery (BA) with acute ischemic lesions on magnetic resonance imaging (MRI) within the vascular territory of the stenosed artery. Exclusion Criteria: Patients with any contraindications to the treatment with antiplatelet therapy Patients with potential cardiac embolic source; prosthetic valve, atrial fibrillation, atrial flutter, left atrial/atrial appendage thrombus, sick sinus syndrome, left ventricular thrombus, dilated cardiomyopathy, akinetic or hypokinetic left ventricular segment, atrial myxoma, Infective endocarditis, mitral valve stenosis or prolapse, mitral annuls calcification, left atrial turbulence, nonbacterial endocarditis, congestive heart failure, recent myocardial infarction (within 4 weeks) Patients with more than 50% stenosis in the parent artery of symptomatic stenosis Bleeding diathesis Chronic liver disease (ALT > 100 or AST > 100) or chronic renal disease (creatinine > 3.0mg/dl) Anemia (hemoglobin < 10mg/dl) or thrombocytopenia (platelet count less than 100,000/mm3) Nonatherosclerotic vasculopathy; patients with clinical characteristics suggesting arterial dissection, moyamoya disease, Takayasu's arteritis, radiation associated angiopathy, and other vasculitis. Severe stroke: NIH stroke scale : more than 16 Pregnant or lactating patients Chronic user of NSAIDs Thrombolytic therapy for the symptomatic stenosis Symptomatic stenosis scheduled for angioplasty Patients with pacemaker or any other contraindications to MRI
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sun U. Kwon, MD, PhD
Organizational Affiliation
Asan Medical Center, Univsersity of Ulsan, Medical College
Official's Role
Principal Investigator
Facility Information:
Facility Name
Prince of Wales Hospital
City
Hong Kong
Country
Hong Kong
Facility Name
Queen Mary Hospital
City
Hong Kong
Country
Hong Kong
Facility Name
Konkuk Univ. Hospital
City
Seoul
State/Province
Gwangjin-gu Hwayang-dong
ZIP/Postal Code
143-729
Country
Korea, Republic of
Facility Name
Inje University Ilsan Paik Hospital
City
Goyang
State/Province
Gyeonggi-do
ZIP/Postal Code
411-706
Country
Korea, Republic of
Facility Name
Dongguk University International Hospital
City
Goyang
State/Province
Kyoungki-do
ZIP/Postal Code
410-773
Country
Korea, Republic of
Facility Name
Hallym University Sacred Heart Hospital
City
Anyang
State/Province
Kyunggi
ZIP/Postal Code
430-070
Country
Korea, Republic of
Facility Name
Inha University Hospital
City
Inchon
ZIP/Postal Code
400-103
Country
Korea, Republic of
Facility Name
Seoul National University Bundang Hospital
City
Seongnam
Country
Korea, Republic of
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Facility Name
Kangdong Sacred Heart Hospital, Hallym University
City
Seoul
ZIP/Postal Code
134-701
Country
Korea, Republic of
Facility Name
Samsung Medical Center
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Asan Medical Center
City
Seoul
ZIP/Postal Code
138-736
Country
Korea, Republic of
Facility Name
Soonchunhyang University Hospital
City
Seoul
ZIP/Postal Code
140-743
Country
Korea, Republic of
Facility Name
Seoul National University Boramae Hospital
City
Seoul
ZIP/Postal Code
156-707
Country
Korea, Republic of
Facility Name
Eulji Hospital
City
Seoul
ZIP/Postal Code
280-1
Country
Korea, Republic of
Facility Name
Philippine General Hospital
City
Manila
Country
Philippines
Facility Name
University of Santo Tomas Hospital
City
Manila
Country
Philippines
Facility Name
Ramathibodi Hospital
City
Bangkok
Country
Thailand
Facility Name
Siriraj Hospital
City
Bangkok
Country
Thailand

12. IPD Sharing Statement

Citations:
PubMed Identifier
24957314
Citation
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.
Results Reference
derived
PubMed Identifier
24315720
Citation
Kim BJ, Rha JH, Kim SR, Kim DE, Kim HY, Lee JH, Bae HJ, Han MK, Kang DW, Ratanakorn D, Kim JS, Kwon SU. The effect of cilostazol on carotid intima-media thickness progression in patients with symptomatic intracranial atherosclerotic stenosis. J Stroke Cerebrovasc Dis. 2014 May-Jun;23(5):1164-70. doi: 10.1016/j.jstrokecerebrovasdis.2013.10.007. Epub 2013 Dec 6.
Results Reference
derived
PubMed Identifier
22910894
Citation
Jung JM, Kang DW, Yu KH, Koo JS, Lee JH, Park JM, Hong KS, Cho YJ, Kim JS, Kwon SU; TOSS-2 Investigators. Predictors of recurrent stroke in patients with symptomatic intracranial arterial stenosis. Stroke. 2012 Oct;43(10):2785-7. doi: 10.1161/STROKEAHA.112.659185. Epub 2012 Aug 21.
Results Reference
derived
PubMed Identifier
22539545
Citation
Kim DE, Kim JY, Jeong SW, Cho YJ, Park JM, Lee JH, Kang DW, Yu KH, Bae HJ, Hong KS, Koo JS, Lee SH, Lee BC, Han MK, Rha JH, Lee YS, Kim GM, Chae SL, Kim JS, Kwon SU. Association between changes in lipid profiles and progression of symptomatic intracranial atherosclerotic stenosis: a prospective multicenter study. Stroke. 2012 Jul;43(7):1824-30. doi: 10.1161/STROKEAHA.112.653659. Epub 2012 Apr 26. Erratum In: Stroke. 2013 Nov;44(11):158.
Results Reference
derived
PubMed Identifier
21799173
Citation
Kwon SU, Hong KS, Kang DW, Park JM, Lee JH, Cho YJ, Yu KH, Koo JS, Wong KS, Lee SH, Lee KB, Kim DE, Jeong SW, Bae HJ, Lee BC, Han MK, Rha JH, Kim HY, Mok VC, Lee YS, Kim GM, Suwanwela NC, Yun SC, Nah HW, Kim JS. Efficacy and safety of combination antiplatelet therapies in patients with symptomatic intracranial atherosclerotic stenosis. Stroke. 2011 Oct;42(10):2883-90. doi: 10.1161/STROKEAHA.110.609370. Epub 2011 Jul 28.
Results Reference
derived

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Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II

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