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

• ClinicalTrials.gov Identifier: NCT04078737
• Recruitment Status: Active, not recruiting
• First Posted: September 6, 2019
• Last Update Posted: September 6, 2019
• Sponsor: Ministry of Science and Technology of the People´s Republic of China
• Information provided by (Responsible Party): Yongjun Wang, MD, Ministry of Science and Technology of the People´s Republic of China

Study Description

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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 6396 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: June 29, 2019
• Estimated Primary Completion Date: September 2021
• Estimated Study Completion Date: June 2022

Arms and Interventions

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

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 (ischemic stroke or hemorrhagic stroke) within 1 year [ Time Frame: 1 year after randomization ]
   Percentage of patients with the 1 year new stroke events (ischemic stroke/ hemorrhagic stroke) as a cluster and evaluated individually.
2. 3-month and 1 year new clinical vascular events [ Time Frame: 3 months and 1 yearafter randomization ]
   Percentage of patients with the 3-month and 1 year new events (ischemic stroke/ hemorrhagic stroke/ TIA/ MI(myocardial infarction)/vascular death)
3. 3-month and 1 year new ischemic stroke events [ Time Frame: 3 months and 1 year after randomization ]
   Percentage of patients with the 3-month and 1 year new ischemic stroke will be evaluated.
4. mRS change [ Time Frame: 3 months and 1 year after randomization ]
   Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6 at 3 month/ 1 year follow-up. 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. Further efficacy exploratory analysis: NIHSS change at 3 months [ Time Frame: 3 months after randomization ]
   Further efficacy exploratory analysis: Impairment (changes in NIHSS scores at 3 month follow-up). The NIHSS is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
6. Further efficacy exploratory analysis: Quality of Life [ 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.

Other Outcome Measures:

1. stratified analysis [ Time Frame: 3-month and 1-year after randomization ]
   Efficacy endpoint will also be analyzed stratified by gender (men vs. women), age (<65 vs. ≥65 years), by etiology subtype based on the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtype system, by diabetes (yes vs. no) and by type of LOF allele (intermediate metabolizers vs. poor metabolizers), status of intracranial and extracranial artery stenosis (yes vs. no).
2. 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.
3. 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.
4. All bleeding events [ Time Frame: 3 months and 1 year after randomization ]
   All bleeding events (severe/moderate bleeding and intracranial hemorrhage)
5. Total mortality [ Time Frame: 3 months and 1 year after randomization ]
   Total mortality
6. Incidence symptomatic and asymptomatic intracranial hemorrhagic events [ Time Frame: 3 months and 1 year after randomization ]
   Incidence symptomatic and asymptomatic intracranial hemorrhagic events
7. Adverse events [ Time Frame: 3 months and 1 year after randomization ]
   Adverse events

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Older than 40 Years ；

2. Acute onset of cerebral ischemia due to

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

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 ASA (• Known allergy •Severe renal or hepatic insufficiency • Severe cardiac failure, asthma • History of Hemostatic disorder or systemic bleeding • History of thrombocytopenia or neutropenia • History of drug-induced hematologic
6. Hematokrit(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 (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 bradyarrhythmic 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. Treatment with ticagrelor or clopidogrel 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 or major surgery within 3 months
22. Diagnosis or suspicious diagnosis of acute coronary syndrome
23. Participation in another clinical study with an investigational product during the last 30 days.
24. Currently receiving an investigational drug or device
25. Pregnant, currently trying to become pregnant, or of child-bearing potential and not using birth control.

Contacts and Locations

Locations

China, Beijing

Beijing Tian tan Hospital

Beijing, Beijing, China, 100070

Sponsors and Collaborators

Ministry of Science and Technology of the People´s Republic of China

Investigators

• Principal Investigator: Yongjun Wang, M.D; Beijing Tian Tan Hospital, Capital Medical University, Beijing, China

More Information

Publications:

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. 2013 Jul 4;369(1):11-9. doi: 10.1056/NEJMoa1215340. Epub 2013 Jun 26.

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.

• Responsible Party: Yongjun Wang, MD, Vice president of Beijing Tiantan Hospital, Ministry of Science and Technology of the People´s Republic of China
• ClinicalTrials.gov Identifier: NCT04078737
• Other Study ID Numbers: 2017ZX09304018001
• First Posted: September 6, 2019
• Last Update Posted: September 6, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yongjun Wang, MD, Ministry of Science and Technology of the People´s Republic of China:

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:

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