Platelet Reactivity in Acute Non-disabling Cerebrovascular Events

Stroke Clinical Trial

— PRINCE  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02506140
• Other study ID #: D151100002015001
• Secondary ID: 81322019
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: August 2015
• Est. completion date: March 2018

Study information

• Verified date: December 2017
• Source: Beijing Tiantan Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 675
• Est. completion date: March 2018
• Est. primary completion date: March 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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%

Related Conditions & MeSH terms

• Ischemia
• Ischemic Attack, Transient
• Stroke

Intervention

Drug:
• Ticagrelor and Acetylsalicylic acid
This 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; combined with Aspirin 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.
• Clopidogrel and Acetylsalicylic acid
This 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; combined with Aspirin 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.

Locations

Country	Name	City	State
China	Aviation General Hospital of China Medical University	Beijing
China	Beijing Tian Tan Hospital, Capital Medical University	Beijing
China	Dongfang Hospital Beijing University of Chinese Medicine	Beijing
China	The First Hospital of Fangshan District,Beijing	Beijing
China	Xiangya Hospital Central South University	Changsha	Hunan
China	Daping Hospital,Third Military Medical University	Chongqing
China	The First Affiliated Hospital of Fujian Medical University	Fuzhou	Fujian
China	Renji Hospital,Shanghai Jiao Tong University School of Medicine	Shanghai
China	General Hospital of Shenyang Military	Shengyang	Liaoning
China	The Second People's Hospital of Shenzhen	Shenzhen	Guangdong
China	The Second Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	General Hospital of TISCO	Taiyuan	Shanxi
China	The Second Hospital of Shanxi Medical University	Taiyuan	Shanxi
China	Taizhou First People's Hospital,Huangyan Hospital of Wenzhou Medical University	Taizhou	Zhejiang
China	North China University of Science And Technology Affiliated Hospital	Tangshan	Hebei
China	Tangshan Gongren Hospital	Tangshan	Hebei
China	Tianjin Huanhu Hospital	Tianjin
China	The First Affiliated Hospital of Wenzhou Medical University	Wenzhou	Zhejiang
China	Wenzhou Hospital of integrated Chinese and Western medicine	Wenzhou	Zhejiang
China	Renmin Hospital of Wuhan University	Wuhan	Hubei
China	Union Hospital,Tongji Medical College,Huazhong University of Science and Technology	Wuhan	Hubei
China	Wuhan Brain Hospital,General Hospital of The Yangtze River Shipping	Wuhan	Hubei
China	Wuhan No.1 Hospital	Wuhan	Hubei
China	Northern Jiangsu People's Hospital,Clinical Medical School,YangZhou University	Yangzhou	Jiangsu
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan

Sponsors (2)

Lead Sponsor	Collaborator
Beijing Tiantan Hospital	Beijing Municipal Science & Technology Commission

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	High on-treatment platelet reactivity (HOPR) defined as P2Y12 reaction unit (PRU)> 208 measured by VerifyNow® assay at 90 days		90 days
Secondary	HOPR at 90 days in subjects carrying genetic variants which affected Clopidogrel metabolism.	HOPR defined as P2Y12 reaction unit (PRU)> 208 measured by VerifyNow® assay	90 days
Secondary	New vascular events defined as any event of the following: Any stroke (ischemic or hemorrhage).	All the new vascular events will be assessed by at least two neurologists based on neuroimaging and clinical feature. When there was disagreement, a third senior neurologist was consulted to reach a consensus decision.	90 days, 6 months, 1 year
Secondary	New composite clinical vascular events (ischemic stroke/ hemorrhagic stroke/TIA/ myocardial infarction/ vascular death) as a cluster.	All the new composite clinical vascular events will be assessed by at least two neurologists based on laboratory examination, imaging and clinical feature. When there was disagreement, a third senior neurologist was consulted to reach a consensus decision.	90 days, 6 months, 1 year
Secondary	High on-treatment platelet reactivity defined as PRU> 208 measured by VerifyNow® assay.		2hours, 24 hours, 7 days
Secondary	High on-treatment platelet reactivity defined as Aspirin reactivity unit (ARU)> 555 measured by VerifyNow® assay.		7 days
Secondary	HOPR defined as Maximum Amplitude-adenosine diphosphate (MA-ADP)>47 measured by Thrombelastography Platelet Mapping Assay (TEG) using the inducer of adenosine diphosphate.		90 days
Secondary	Residual platelet reactivity defined as the value of PRU.		2hours, 24 hours, 7 days, 90 days
Secondary	Residual platelet reactivity defined as the value of Aspirin reaction unit (ARU).		7days
Secondary	Residual platelet reactivity defined as the value of MA-ADP.		7days, 90 days
Secondary	Residual platelet reactivity defined as the value of Maximum Amplitude- acetylsalicylic acid (MA-AA) measured by TEG.		7days
Secondary	Residual platelet reactivity change from baseline in PRU.		2hours, 24 hours, 7 days, 90 days
Secondary	Residual platelet reactivity change from baseline in ARU.		7 days
Secondary	The inhibition of platelet aggregation (IPA) measured by VerifyNow® assay.		2hours, 24 hours, 7 days, 90 days
Secondary	The TEG-platelet inhibition(TPI)measured by TEG.		7 days, 90 days
Secondary	Platelet inhibition change from baseline in IPA.		2hours, 24 hours, 7 days, 90 days
Secondary	Platelet inhibition change from baseline in TPI.		7 days, 90 days
Secondary	Residual platelet reactivity detected by AspirinWorks.		7days
Secondary	Residual platelet reactivity detected by PL Platelet Analyser (SINNOWA®).		7days, 90days
Secondary	Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6.		90 days, 6 months, 1 year
Secondary	Further efficacy exploratory analysis:Impairment (changes in NIHSS scores at 90 days, 6 months, 1 year follow-up)		90 days, 6 months, 1 year
Secondary	Further efficacy exploratory analysis:Quality of Life (The EuroQol-5D 3 level version[EQ-5D-3L]scale).		90 days, 6 months, 1 year
Secondary	Major bleed (PLATO definition), including fatal/life-threatening and other.	The PLATO(Platelet Inhibition and Patient Outcomes) definition of fatal/life-threatening of major bleed is any one of the following: Fatal, Intracranial, Intrapericardial bleed with cardiac tamponade, Hypovolaemic shock or severe hypotension due to bleeding and requiring pressors or surgery, Clinically overt or apparent bleeding associated with a decrease in hemoglobin(Hb) of more than50 g/L, Transfusion of 4 or more units (whole blood or packed red blood cells [PRBCs]) for bleeding. The PLATO definition of other of major bleed is any one of the following:Significantly disabling (eg. intraocular with permanent vision loss), Clinically overt or apparent bleeding associated with a decrease in Hb of 30 g/L to 50 g/L, Transfusion of 2-3 units (whole blood or PRBCs) for bleeding.	90 days, 6 months, 1 year
Secondary	Intracranial hemorrhagic events.	Intracranial hemorrhagic events is assessed by brain computed tomography (CT) or gradient recalled echo (GRE) T2 star weighted MRI.	90 days, 6 months, 1 year
Secondary	Total mortality.	All deaths reported post-randomization will be recorded and adjudicated. Deaths will be subclassified by the adjudication committee as cardiovascular or non-cardiovascular.	90 days, 6 months, 1 year