Platelet Reactivity in Acute Non-disabling Cerebrovascular Events
Platelet Reactivity in Acute Non-disabling Cerebrovascular Events
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%