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Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II (CHANCE-2)

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ClinicalTrials.gov Identifier: NCT04078737
Recruitment Status : Completed
First Posted : September 6, 2019
Last Update Posted : December 2, 2021
Sponsor:
Collaborator:
Ministry of Science and Technology of the People´s Republic of China
Information provided by (Responsible Party):
Yongjun Wang, Beijing Tiantan Hospital

Study Description
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Brief Summary:
The primary objective of this trial is to assess the effects of ticagrelor plus aspirin versus clopidogrel plus aspirin on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in CYP2Y19 LOF alleles carriers with TIA or minor stroke.

Condition or disease Intervention/treatment Phase
Stroke Transient Ischemic Attack Drug: Ticagrelor and Aspirin Drug: Clopidogrel and Aspirin Phase 3

Detailed Description:

According to the Global Burden of Disease(GBD) Study 2016, China bears the greatest lifetime risk of stroke from 25-year-age onward. Minor ischemic events, including minor stroke and TIA, were major parts of stroke manifestations. Events (CHANCE) has shown that 21-day dual antiplatelet therapy (clopidogrel and aspirin) compared to aspirin alone which initiated within 24 hours after symptoms onset would reduce 32% risk of stroke recurrence within 90 day, but not in carriers of CYP2C19 loss-of-function (LOF) alleles. The primary purpose of this study is to compare ticagrelor plus aspirin with clopidogrel plus aspirin on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in CYP2Y19 LOF alleles carriers with TIA or minor stroke.

Both intent analysis (ITT) and compliance program set (PPS) were used for analysis.

We will use Kaplan-Meier estimates of the cumulative risk of stroke (ischemic or hemorrhagic) event during maximum 90-day follow-up, with hazards ratios and 95% CI calculated using Cox proportional hazards methods and the log-rank test to evaluate the treatment effect. All statistics will be 2-sided with P<0.05 considered significant, accounting for interim analyses.

All patients who received study drugs and with at least one safety follow-up record will be included in the safety population. The data for safety evaluation included adverse reactions observed during the trial and changes in laboratory data before and after treatment.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6412 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II
Actual Study Start Date : September 23, 2019
Actual Primary Completion Date : June 24, 2021
Actual Study Completion Date : July 1, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Ticagrelor plus Aspirin Group
Ticagrelor of loading dosing of 180mg followed by 90mg bid for 3 months plus aspirin of loading dose of 75-300mg followed by 75mg daily for 21 days
 Drug: Ticagrelor and Aspirin

Day of randomization:

Day1:Ticagrelor 180mg; placebo of clopidogrel 300mg; aspirin 75-300mg (open label) Day2-21st: Ticagrelor 90mg bid/day; placebo of clopidogrel 75mg; aspirin 75mg (open label) Day 22nd-3 months:Ticagrelor 90mg bid/day; placebo of clopidogrel 75mg
Active Comparator: Clopidogrel plus Aspirin Group
Clopidogrel of loading dosing of 300mg followed by 75mg daily for 3 months plus aspirin loading dose of 75-300mg followed by 75mg daily for 21 days
 Drug: Clopidogrel and Aspirin

Day of randomization:

Day 1: Clopidogrel 300mg; placebo of ticagrelor 180mg; aspirin 75-300mg (open label) Day2-21st: Clopidogrel 75mg/day; placebo of ticagrelor 90mg bid/day; aspirin 75mg (open label) Day 22nd-3 months:Clopidogrel 75mg; placebo of ticagrelor 90mg bid/day


Outcome Measures
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Primary Outcome Measures :
  1. Any new stroke events (ischemic stroke or hemorrhagic stroke) within 3 months [ Time Frame: 3 months after randomization ]
    The aim is to assess the effects of ticagrelor plus aspirin versus clopidogrel plus aspirin on reducing the 3-month risk of any stroke (both ischemic and hemorrhagic, primary outcome) when initiated within 24 hours of symptom onset in CYP2Y19 LOF alleles carriers with TIA or minor stroke.


Secondary Outcome Measures :
  1. Any new stroke events within 30 days and 1 year [ Time Frame: 30 days and 1 year after randomization ]
    Percentage of patients with the 30 days and 1 year new stroke events (ischemic stroke/ hemorrhagic stroke) as a cluster and evaluated individually.

  2. New clinical vascular events including stroke, TIA, myocardial infarction, and vascular deaths within 3 months and 1 year [ Time Frame: 3 months and 1 year after randomization ]
    Percentage of patients with the 3 months and 1 year new clinical vascular events (ischemic stroke/ hemorrhagic stroke/ TIA/ myocardial infarction/vascular death)

  3. New ischemic stroke within 3 months and 1 year [ Time Frame: 3 months and 1 year after randomization ]
    Percentage of patients with the 3 months and 1 year new ischemic stroke will be evaluated.

  4. Disabling stroke (Modified Rankin Scale score, mRS>1) at 3 months and 1 year [ Time Frame: 3 months and 1 year after randomization ]
    Modified Rankin Scale, a commonly used scale for measuring the degree of dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. 0 - No symptoms.1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.3 - Moderate disability. Requires some help, but able to walk unassisted.4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.6 - Dead. The mRS scores between 3 to 6 points are considered to be poor functional outcome. (dead).

  5. Incidence and severity of recurrent stroke and TIA during follow-up to 3 months and 1-year [ Time Frame: 3 months and 1 year after randomization ]
    (Severity is measured using a six-level ordered categorical scale that incorporates the mRS: fatal stroke/severe non-fatal stroke [mRS 4 or 5]/moderate stroke [mRS 2 or 3]/mild stroke [mRS 0 or 1]/TIA/no stroke-TIA).

  6. Neurological impairment at 3 months (NIHSS increased≥4 from baseline) [ Time Frame: 3 months after randomization ]
    The National Institutes of Health Stroke Scale (NIHSS) score classifies neurologic deficit from 0 (no deficit) to 42 (most severe).

  7. Quality of Life (EuroQol EQ-5D scale) at 3 months and at 1 year [ Time Frame: 3 months and 1 year after randomization ]
    Further efficacy exploratory analysis:Quality of Life (EuroQol EQ-5D scale). We will use the EQ-5D-5L scale to evaluate the quality of life. EQ-5D-5L is a standardized instrument for measuring generic health status. It has been widely used in population health surveys, clinical studies, economic evaluation and in routine outcome measurement in the delivery of operational healthcare. The EQ-5D-5L has five domain scales (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression) and five levels for each domain.

  8. Stratified analysis [ Time Frame: 3 months and 1 year after randomization ]
    The influence on treatment effect of age, gender, Body Mass Index (BMI), index event type (TIA vs. minor stroke), time from index event to randomization, etiology subtype, diabetes mellitus, hypertension, type of LOF allele, previous ischemic stroke or TIA, prior antiplatelet therapy, prior statin therapy, prior smoking status, and symptomatic intracranial and extracranial artery stenosis will be evaluated in subgroup analyses.


Other Outcome Measures:
  1. Moderate and severe bleeding events according to the GUSTO criteria [ Time Frame: 3 months after randomization ]
    Severe bleeding incidence (GUSTO definition), including fatal bleeding and symptomatic intracranial hemorrhage.

  2. Moderate and severe bleeding events according to the GUSTO criteria [ Time Frame: 1 year after randomization ]
    Severe bleeding incidence (GUSTO definition), including fatal bleeding and symptomatic intracranial hemorrhage.

  3. All bleeding events [ Time Frame: 3 months and 1 year after randomization ]
    All bleeding events (severe/moderate bleeding and intracranial hemorrhage)

  4. Total mortality [ Time Frame: 3 months and 1 year after randomization ]
    Total mortality

  5. Incidence symptomatic intracranial hemorrhagic events [ Time Frame: 3 months and 1 year after randomization ]
    Incidence symptomatic intracranial hemorrhagic events

  6. Adverse events [ Time Frame: 3 months and 1 year after randomization ]
    Adverse events


Eligibility Criteria
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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. 40 years or older than 40 years；

  2. Acute cerebral ischemic event due to：

    • Acute non-disabling ischemic stroke (NIHSS≤3 at the time of randomization)or，
    • TIA with moderate-to-high risk of stroke (ABCD2 score ≥ 4 at the time of randomization)；
  3. Can be treated with study drug within 24 hours of symptoms onset*(*Symptom onset is defined by the "last seen normal" principle)；
  4. CYP2C19 loss-of-function allele carriers；
  5. Informed consent signed.

Exclusion Criteria

  1. Malformation, tumor, abscess or other major non-ischemic brain disease (e.g., multiple sclerosis) on baseline head CT or MRI.
  2. 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.
  3. Iatrogenic causes (angioplasty or surgery) of minor stroke or TIA.
  4. Preceding moderate or severe dependency (modified Rankin scale [mRS] score 3-5).

  5. Contraindication to clopidogrel, ticagrelor or aspirin

    • Known allergy
    • Severe renal (creatinine exceeding 1.5 times of the upper limit of normal range) or hepatic (ALT or AST > twice the upper limit of normal range) insufficiency
    • Severe cardiac failure (NYHA level: III to IV)
    • History of hemostatic disorder or systemic bleeding
    • History of thrombocytopenia or neutropenia
    • History of drug-induced hematologic disorder or hepatic dysfunction
    • Low white blood cell (<2×109/L) or platelet count (<100×109/L)
  6. Hematocrit (HCT) <30%
  7. Clear indication for anticoagulation (presumed cardiac source of embolus, e.g., atrial fibrillation, prosthetic cardiac valves known or suspected endocarditis)
  8. History of intracranial hemorrhage or amyloid angiopathy
  9. History of aneurysm (including intracranial aneurysm and peripheral aneurysm)
  10. History of asthma or COPD (chronic obstructive pulmonary disease)
  11. High-risk for bradyarrhythmia (first-degree or second-degree AV block caused by sinus node disease, and brady-arrhythmic syncope without pacemaker)
  12. History of hyperuricemia nephropathy
  13. Anticipated requirement for long-term (>7 days) non-steroidal anti-inflammatory drugs (NSAIDs)
  14. Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months
  15. Scheduled for surgery or interventional treatment requiring study drug cessation
  16. Severe non-cardiovascular comorbidity with life expectancy < 3 months
  17. Inability to understand and/or follow research procedures due to mental, cognitive, or emotional disorders
  18. Dual antiplatelet treatment (or more than two antiplatelet agents) in 72 hours before randomization
  19. Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anti coagulation
  20. Intravenous thrombolytic therapy (such as intravenous rtPA) or mechanical thrombectomy within 24 hours prior to randomization
  21. Gastrointestinal bleed within 3 months or major surgery within 30 days
  22. Diagnosis or suspicious diagnosis of acute coronary syndrome
  23. Participation in another clinical study with an experimental product during the last 30 days
  24. Currently receiving an experimental drug or device
  25. Pregnant, currently trying to become pregnant, or of child-bearing potential and not using birth control
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04078737


Locations
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Sponsors and Collaborators
Beijing Tiantan Hospital
Ministry of Science and Technology of the People´s Republic of China
Investigators
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Principal Investigator: Yongjun Wang, M.D Beijing Tian Tan Hospital, Capital Medical University, Beijing, China
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Yongjun Wang, President of Beijing Tiantan Hospital, Beijing Tiantan Hospital
ClinicalTrials.gov Identifier: NCT04078737    
Obsolete Identifiers: NCT04952311
Other Study ID Numbers: 2017ZX09304018001
First Posted: September 6, 2019    Key Record Dates
Last Update Posted: December 2, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yongjun Wang, Beijing Tiantan Hospital:
stroke
transient ischemic attack
acute treatment
acute non-disabling cerebrovascular event
clopidogrel
 ticagrelor
clopidogrel combined with ASA
ticagrelor combined with ASA
recurrence of stroke and other vascular events
CYP2C19 loss-of-function allele(s) carrier
Additional relevant MeSH terms:
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Ischemic Attack, Transient
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Brain Ischemia
Aspirin
Clopidogrel
Ticagrelor
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
 Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents