Ticagrelor is a reversible and direct-acting oral antagonist of the P2Y12 (Purinergic receptor P2Y, G-protein coupled, 12) receptor for adenosine diphosphate, which provides faster, greater, and more consistent P2Y12 inhibition than Clopidogrel in patients with acute coronary syndrome, irrespective of the genetic variants affecting Clopidogrel metabolism. It is still undefined whether combination therapy of Ticagrelor and Aspirin is more effective than Clopidogrel and aspirin for minor stroke and transient ischemic attack (TIA). The primary purpose of the PRINCE trial is to evaluate the anti-platelet effects of a 3-month regimen of ticagrelor initiated with 180 mg loading dose followed by 90 mg twice/day combined with aspirin 100 mg/day during first 21 days versus a 3-month regimen of clopidogrel initiated with 300 mg loading dose of followed by 75 mg/day combined with aspirin 100 mg/day during first 21 days when initiated within 24 hours of symptom onset in high-risk transient ischemic attack or minor stroke.

The PRINCE trial is a prospective, randomized, multi-centre, open-label, active-controlled, blinded-endpoint trial (a PROBE design concerning clinical trial). A total of approximately 952 patients (40years≤Age<80years) with high-risk TIA (defined as an ABCD2 score ≥ 4 or the stenosis of offending vessel ≥ 50%) or minor ischemic stroke (defined as an NIHSS ≤ 3), who can be treated within 24 hours of symptom onset will be enrolled. Patients fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomized 1:1 into two groups after offering informed content: 1) one group will receive a 180 mg loading dose of ticagrelor on the day of randomization, followed by 90 mg twice/day ticagrelor from Day 2 to 3 months; 2) the other group will receive a 300 mg loading dose of clopidogrel on the day of randomization, followed by 75 mg once/day clopidogrel from Day 2 to 3 months. Aspirin will be given in a total dose of 100-300 mg on the first day, followed by 100 mg once/day from Day 2 to Day 21 in the both groups. The primary objective is to assess the anti-platelet effects of Ticagrelor combined with Aspirin versus Clopidogrel combined with Aspirin in Chinese patients with high-risk TIA and minor stroke. The study consists of six visits including the day of randomization, 2 hours after the first anti-platelet agents, 24 hours after the first anti-platelet agents, Day 7+2days, Day 21±2days and Day 90±7days. Genomic DNA of all patients will be collected for genotyped. And the genetic variants affecting Clopidogrel metabolism will be analyzed. The antiplatelet effects will be analyzed in total subjects and genetic variants carriers. The trial is anticipated to complete in 18 months from the first subject recruitment , with 952 subjects recruited from 25 centres in China. A Data and Safety Monitoring Board (DSMB) will regularly monitor safety during the study. The trial has been approved by IRB(Institutional Review Board) /EC(Ethics Committee) in Beijing Tiantan hospital, Capital Medical University.

Inclusion Criteria:

1. Provision of informed consent.
2. Female or male aged≥ 40 years and <80 years.
3. 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 defined by the"last see normal"principle.
4. 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 or the stenosis of offending vessel ≥ 50%).

Exclusion Criteria:

1. 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 Computed Tomography (CT) or magnetic resonance imaging (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. Modified Rankin Scale Score > 2 at randomization (pre-morbid historical assessment)。

4. Contraindication to ticagrelor, clopidogrel or acetylsalicylic acid :

   • Known hypersensitivity
   • Severe renal or hepatic insufficiency
   • Severe cardiac failure, asthma
   • Hemostatic disorder or systemic bleeding
   • History of hemostatic disorder or systemic bleeding
   • History of drug-induced hematologic or hepatic abnormalities
   • Low white blood cell (<2 x10^9/L) or platelet count (<100 x10^9/L)

5. Clear indication for anticoagulation (presumed cardiac source of embolus, e.g., atrial fibrillation, ventricular aneurysm, prosthetic cardiac valves known, suspected endocarditis or other suspicion of cardioembolic pathology for TIA/stroke).

6. Continuous use of ticagrelor or clopidogrel over 5 days before randomization

7. Current treatment (last dose given within 10 days before randomization) with heparin therapy or anti coagulation therapy (e.g., warfarin; thrombin inhibitors such as dabigatran , argatroban, bivalirudin, ximelagatran; factor Xa inhibitors such as rivaroxaban, edoxaban, apixaban, betrixaban, tanexaban ; hirudin; unfractionated and low molecular weight heparins ).

8. Receipt of intravenous/ intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomization.

9. History of intracranial hemorrhage or cerebral artery amyloidosis.

10. History of aneurysm (including intracranial aneurysm or peripheral aneurysms)

11. Diagnosis or of acute coronary syndrome.

12. History of asthma or COPD (chronic obstructive pulmonary disease).

13. High risk of bradyarrhythmia, such as sick sinus syndrome second-degree or third-degree atrioventricular block, bradycardia-related syncope without installed pacemaker.

14. History of uric acid nephropathy.

15. Anticipated requirement for long-term (>7 days) non-study anti-platelet drugs, or NSAIDs (nonsteroidal antiinflammatory drugs) affecting platelet function.

16. History of previous symptomatic non-traumatic intracerebral bleed at any time (asymptomatic microbleeds do not qualify), gastrointestinal (GI) bleed within the past 3 months, or major surgery within 30 days.

17. Qualifying TIA or minor stroke induced by angiography or surgery.

18. Planned or likely revascularization within the next 3 months.

19. Scheduled for surgery or interventional treatment requiring study drug cessation.

20. Severe non-cardiovascular comorbidity with life expectancy < 3 months.

21. Pregnancy or lactation, and women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test.

22. Currently receiving an investigational drug or device.

23. Participation in another clinical study with an investigational product during the last 30 days.

24. Inability of the patient to understand and/or comply with study procedures and/or follow-up, in the opinion of the Investigator.

25. Hematocrit (Hct) < 30%