Clopidogrel in High-risk Patients With Acute Non-disabling Cerebrovascular Events

Stroke Clinical Trial

— CHANCE  

Official title:

Randomized,Double-blind Trial Comparing the Effects of a 3-month Clopidogrel Regimen,Combined With ASA During the First 21days,Versus ASA Alone for the Acute Treatment of TIA or Minor Stroke

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00979589
• Other study ID #: 2008ZX09312-008
• Status: Completed
• Phase: Phase 3
• Start date: December 2009
• Est. completion date: June 2012

Study information

• Verified date: July 2020
• Source: Beijing Tiantan Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the effects of a 3-month regimen of clopidogrel initiated with a loading dose (LD) of 300 mg followed by 75 mg/day during the first 21days versus a 3-month regimen of ASA 75 mg/day alone on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in high-risk patients with TIA or minor stroke.

Description:

Inclusion criteria:

1. Adult subjects (male or female ≥ 40 years)

2. Acute non-disabling ischemic stroke (NIHSS≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle.

3. TIA (Neurological deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with study drug within 24 hours of symptoms onset and with moderate-to-high risk of stroke recurrence (ABCD2 score ≥ 4 at the time of randomization). Symptom onset is defined by the "last see normal" principle.

4. Informed consent signed

Primary Efficacy Endpoint:

Percentage of patients with the 3-month new vascular events, defined as any event of the following:Any stroke (ischemic or hemorrhage).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5100
• Est. completion date: June 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 90 Years

Eligibility

Inclusion criteria:

• Adult subjects (male or female=40 years)

• Acute non-disabling ischemic stroke (NIHSS=3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle

• TIA (Neurological deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with study drug within 24 hours of symptoms onset and with moderate-to-high risk of stroke recurrence (ABCD2 score=4 at the time of randomization).Symptom onset is defined by the "last see normal" principle

• Informed consent signed

Exclusion Criteria:

• Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major non-ischemic brain disease (e.g., multiple sclerosis) on baseline head CT or MRI

• Isolated or pure sensory symptoms (e.g., numbness), isolated visual changes, or isolated dizziness/vertigo without evidence of acute infarction on baseline head CT or MRI

• Modified Rankin Scale Score>2 at randomization (pre-morbid historical assessment)

• NIH Stroke Score=4 at randomization

• Clear indication for anticoagulation(presumed cardiac source of embolus, e.g., atrial fibrillation, prosthetic cardiac valves known or suspected endocarditis)

• Contraindication to clopidogrel or ASA

• Known allergy

• Severe renal or hepatic insufficiency

• Severe cardiac failure, asthma

• Hemostatic disorder or systemic bleeding

• History of hemostatic disorder or systemic bleeding

• History of thrombocytopenia or neutropenia

• History of drug-induced hematologic or hepatic abnormalities

• Low white blood cell (<2 x109/l) or platelet count (<100 x109/l)

• Use of thrombolysis within 24 hours prior to randomization

• History of intracranial hemorrhage

• Anticipated requirement for long-term non-study antiplatelet drugs, or NSAIDs affecting platelet function

• Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anti coagulation

• Gastrointestinal bleed or major surgery within 3 months

• Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months (if clinically indicated, vascular imaging should be performed prior to randomization whenever possible)

• Scheduled for surgery or interventional treatment requiring study drug cessation

• Qualifying TIA or minor stroke induced by angiography or surgery

• Severe non-cardiovascular comorbidity with life expectancy < 3 months

• Women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test

• Currently receiving an investigational drug or device

Related Conditions & MeSH terms

• Ischemic Attack, Transient
• Stroke
• Transient Ischemic Attack

Intervention

Drug:
• Clopidogrel
The first group will receive a 300mg loading dose (LD) of clopidogrel on the day of randomization, followed by 75 mg clopidogrel/day from Day 2 to 3 months. ASA will be given in a total dose ranging between 75 mg and 300 mg (open label) on the first day, followed by blinded 75 mg once /day from Day 2 to Day 21st. Between Day 21st and 3-month visits, ASA 75 mg will be replaced by a placebo of ASA 75 mg.
• Placebo of clopidogrel and Asprin
The second group will receive open label ASA in a total dose ranging between 75 mg and 300 mg on the first day, followed by blinded 75 mg once /day from Day 2 to 3 months. A placebo for clopidogrel will be given from the day of randomization until the 3-month visit.

Locations

Country	Name	City	State
China	Beijing Tian Tan Hospital, Capital Medical University	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Beijing Tiantan Hospital	University of California, San Francisco

Country where clinical trial is conducted

China, 

References & Publications (8)

Jing J, Meng X, Zhao X, Liu L, Wang A, Pan Y, Li H, Wang D, Johnston SC, Wang Y, Wang Y. Dual Antiplatelet Therapy in Transient Ischemic Attack and Minor Stroke With Different Infarction Patterns: Subgroup Analysis of the CHANCE Randomized Clinical Trial. JAMA Neurol. 2018 Jun 1;75(6):711-719. doi: 10.1001/jamaneurol.2018.0247. — View Citation

Li J, Wang A, Zhao X, Liu L, Meng X, Lin J, Jing J, Zou X, Wang Y, Wang Y; CHANCE Investigators. High-sensitive C-reactive protein and dual antiplatelet in intracranial arterial stenosis. Neurology. 2018 Feb 6;90(6):e447-e454. doi: 10.1212/WNL.0000000000004928. Epub 2018 Jan 12. — View Citation

Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ, Liu L, Dietrich D, Wang Y, Johnston SC. Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack: A Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials. JAMA Neurol. 2019 Aug 19. doi: 10.1001/jamaneurol.2019.2531. [Epub ahead of print] Erratum in: JAMA Neurol. 2019 Sep 30;:. — View Citation

Pan Y, Jing J, Chen W, Meng X, Li H, Zhao X, Liu L, Wang D, Johnston SC, Wang Y, Wang Y; CHANCE investigators. Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE. Neurology. 2017 May 16;88(20):1906-1911. doi: 10.1212/WNL.0000000000003941. Epub 2017 Apr 19. Erratum in: Neurology. 2019 Aug 13;93(7):322. — View Citation

Pan Y, Meng X, Jing J, Li H, Zhao X, Liu L, Wang D, Johnston SC, Wang Y, Wang Y; CHANCE Investigators. Association of multiple infarctions and ICAS with outcomes of minor stroke and TIA. Neurology. 2017 Mar 14;88(11):1081-1088. doi: 10.1212/WNL.0000000000003719. Epub 2017 Feb 15. — View Citation

Wang Y, Johnston SC; CHANCE Investigators. Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event. Am Heart J. 2010 Sep;160(3):380-386.e1. doi: 10.1016/j.ahj.2010.05.017. — View Citation

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 201 — View Citation

Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, Pan Y, Liu L, Wang D, Wang C, Meng X, Xu J, Wang Y; CHANCE investigators. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA. 2016 Jul 5;316(1):70-8. doi: 10.1001/jama.2016.8662. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients with the 3-month new vascular events, defined as any event of the following: Any stroke (ischemic or hemorrhage)		3 months
Secondary	Percentage of patients with the 3-month new clinical vascular events (ischemic stroke/ hemorrhagic stroke/ TIA/ MI/ vascular death) as a cluster and evaluated individually.		3 months
Secondary	Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6 at 3 month follow-up		3 months
Secondary	Further efficacy exploratory analysis:Impairment (changes in NIHSS scores at 3 month follow-up).		3 months
Secondary	Further efficacy exploratory analysis:Quality of Life (EuroQol EQ-5D scale)		3 months
Secondary	Efficacy endpoint will also be analyzed stratified by etiological subtypes, by time randomization (< 12 hours vs. = 12 hours), by qualifying event (TIA vs. minor stroke), and by age		3 months
Secondary	Severe bleeding incidence (GUSTO definition), including fatal bleeding and symptomatic intracranial hemorrhage.		3 months
Secondary	Incidence symptomatic and asymptomatic intracranial hemorrhagic events at 3 months		3 months
Secondary	Intracranial hemorrhage		3 months
Secondary	Total mortality		3 months