Clinical trial NCT02506140: Platelet Reactivity in Acute Non-disabling Cerebrovascular Events
Official title: A Randomized, Open-label, Active-Controlled and Blinded-Endpoint Trial Comparing the Antiplatelet Effects of Ticagrelor Plus Aspirin Versus Clopidogrel Plus Aspirin in Chinese Patients With High-risk Transient Ischemic Attack or Minor Stroke.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Stroke
Ischemic Attack, Transient
Keywords: minor stroke
transient ischemic attack
ticagrelor
clopidogrel
dual anti-platelet therapy
platelet reactivity
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Beijing Municipal Science & Technology Commission
First posted: 2015-07-23
Enrollment: 675
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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%

Primary outcomes:
measure: High on-treatment platelet reactivity (HOPR) defined as P2Y12 reaction unit (PRU)> 208 measured by VerifyNow® assay at 90 days
timeFrame: 90 days
Secondary outcomes:
measure: HOPR at 90 days in subjects carrying genetic variants which affected Clopidogrel metabolism.
timeFrame: 90 days
measure: New vascular events defined as any event of the following: Any stroke (ischemic or hemorrhage).
timeFrame: 90 days, 6 months, 1 year
measure: New composite clinical vascular events (ischemic stroke/ hemorrhagic stroke/TIA/ myocardial infarction/ vascular death) as a cluster.
timeFrame: 90 days, 6 months, 1 year
measure: High on-treatment platelet reactivity defined as PRU> 208 measured by VerifyNow® assay.
timeFrame: 2hours, 24 hours, 7 days
measure: High on-treatment platelet reactivity defined as Aspirin reactivity unit (ARU)> 555 measured by VerifyNow® assay.
timeFrame: 7 days
measure: HOPR defined as Maximum Amplitude-adenosine diphosphate (MA-ADP)>47 measured by Thrombelastography Platelet Mapping Assay (TEG) using the inducer of adenosine diphosphate.
timeFrame: 90 days
measure: Residual platelet reactivity defined as the value of PRU.
timeFrame: 2hours, 24 hours, 7 days, 90 days
measure: Residual platelet reactivity defined as the value of Aspirin reaction unit (ARU).
timeFrame: 7days
measure: Residual platelet reactivity defined as the value of MA-ADP.
timeFrame: 7days, 90 days
measure: Residual platelet reactivity defined as the value of Maximum Amplitude- acetylsalicylic acid (MA-AA) measured by TEG.
timeFrame: 7days
measure: Residual platelet reactivity change from baseline in PRU.
timeFrame: 2hours, 24 hours, 7 days, 90 days
measure: Residual platelet reactivity change from baseline in ARU.
timeFrame: 7 days
measure: The inhibition of platelet aggregation (IPA) measured by VerifyNow® assay.
timeFrame: 2hours, 24 hours, 7 days, 90 days
measure: The TEG-platelet inhibition(TPI)measured by TEG.
timeFrame: 7 days, 90 days
measure: Platelet inhibition change from baseline in IPA.
timeFrame: 2hours, 24 hours, 7 days, 90 days
measure: Platelet inhibition change from baseline in TPI.
timeFrame: 7 days, 90 days
measure: Residual platelet reactivity detected by AspirinWorks.
timeFrame: 7days
measure: Residual platelet reactivity detected by PL Platelet Analyser (SINNOWA®).
timeFrame: 7days, 90days
measure: Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6.
timeFrame: 90 days, 6 months, 1 year
measure: Further efficacy exploratory analysis:Impairment (changes in NIHSS scores at 90 days, 6 months, 1 year follow-up)
timeFrame: 90 days, 6 months, 1 year
measure: Further efficacy exploratory analysis:Quality of Life (The EuroQol-5D 3 level version[EQ-5D-3L]scale).
timeFrame: 90 days, 6 months, 1 year
measure: Major bleed (PLATO definition), including fatal/life-threatening and other.
timeFrame: 90 days, 6 months, 1 year
measure: Intracranial hemorrhagic events.
timeFrame: 90 days, 6 months, 1 year
measure: Total mortality.
timeFrame: 90 days, 6 months, 1 year
Other outcomes:
Locations:
city: Fuzhou
country: China
facility: The First Affiliated Hospital of Fujian Medical University
state: Fujian
city: Shenzhen
country: China
facility: The Second People's Hospital of Shenzhen
state: Guangdong
city: Shijiazhuang
country: China
facility: The Second Hospital of Hebei Medical University
state: Hebei
city: Tangshan
country: China
facility: North China University of Science And Technology Affiliated Hospital
state: Hebei
city: Tangshan
country: China
facility: Tangshan Gongren Hospital
state: Hebei
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: Wuhan Brain Hospital,General Hospital of The Yangtze River Shipping
state: Hubei
city: Wuhan
country: China
facility: Union Hospital,Tongji Medical College,Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Wuhan No.1 Hospital
state: Hubei
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital Central South University
state: Hunan
city: Yangzhou
country: China
facility: Northern Jiangsu People's Hospital,Clinical Medical School,YangZhou University
state: Jiangsu
city: Shengyang
country: China
facility: General Hospital of Shenyang Military
state: Liaoning
city: Taiyuan
country: China
facility: The Second Hospital of Shanxi Medical University
state: Shanxi
city: Taiyuan
country: China
facility: General Hospital of TISCO
state: Shanxi
city: Taizhou
country: China
facility: Taizhou First People's Hospital,Huangyan Hospital of Wenzhou Medical University
state: Zhejiang
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
city: Wenzhou
country: China
facility: Wenzhou Hospital of integrated Chinese and Western medicine
state: Zhejiang
city: Beijing
country: China
facility: Aviation General Hospital of China Medical University
city: Beijing
country: China
facility: Beijing Tian Tan Hospital, Capital Medical University
city: Beijing
country: China
facility: Dongfang Hospital Beijing University of Chinese Medicine
city: Beijing
country: China
facility: The First Hospital of Fangshan District,Beijing
city: Chongqing
country: China
facility: Daping Hospital,Third Military Medical University
city: Shanghai
country: China
facility: Renji Hospital,Shanghai Jiao Tong University School of Medicine
city: Tianjin
country: China
facility: Tianjin Huanhu Hospital
Study officials:
References:
citation: Yang Y, Chen W, Pan Y, Yan H, Meng X, Liu L, Wang Y, Wang Y. Ticagrelor Is Superior to Clopidogrel in Inhibiting Platelet Reactivity in Patients With Minor Stroke or TIA. Front Neurol. 2020 Jun 10;11:534. doi: 10.3389/fneur.2020.00534. eCollection 2020.
citation: Yang Y, Chen W, Meng X, Liu L, Wang Y, Pan Y, Wang Y. Impact of smoking on platelet function of ticagrelor versus clopidogrel in minor stroke or transient ischaemic attack. Eur J Neurol. 2020 May;27(5):833-840. doi: 10.1111/ene.14171. Epub 2020 Mar 8.
citation: Wang Y, Chen W, Lin Y, Meng X, Chen G, Wang Z, Wu J, Wang D, Li J, Cao Y, Xu Y, Zhang G, Li X, Pan Y, Li H, Zhao X, Liu L, Lin J, Dong K, Jing J, Johnston SC, Wang D, Wang Y; PRINCE Protocol Steering Group. Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: open label, blinded endpoint, randomised controlled phase II trial. BMJ. 2019 Jun 6;365:l2211. doi: 10.1136/bmj.l2211.
citation: Wang Y, Lin Y, Meng X, Chen W, Chen G, Wang Z, Wu J, Wang D, Li J, Cao Y, Xu Y, Zhang G, Li X, Pan Y, Li H, Liu L, Zhao X, Wang Y; PRINCE Protocol Steering Group. Effect of ticagrelor with clopidogrel on high on-treatment platelet reactivity in acute stroke or transient ischemic attack (PRINCE) trial: Rationale and design. Int J Stroke. 2017 Apr;12(3):321-325. doi: 10.1177/1747493017694390. Epub 2017 Jan 1.