Platelet Reactivity in Acute Non-disabling Cerebrovascular Events

NCT ID: NCT02506140

Last Updated: 2020-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 675 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-31
• Study Completion Date: 2018-03-31

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.

Conditions

Stroke; Ischemic Attack, Transient

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Ticagrelor/ASA

Drugs: Ticagrelor and Acetylsalicylic acid.

Group Type: EXPERIMENTAL

Ticagrelor and Acetylsalicylic acid

Intervention Type: DRUG

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/ASA

Drugs: Clopidogrel and Acetylsalicylic acid.

Group Type: ACTIVE_COMPARATOR

Clopidogrel and Acetylsalicylic acid

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

BRILINTA; Aspirin; Plavix; Aspirin

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%

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beijing Municipal Science & Technology Commission

OTHER

Sponsor Role: collaborator

Beijing Tiantan Hospital

OTHER

Sponsor Role: lead

Responsible Party

Yongjun Wang

Executive Vice-President

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

The First Affiliated Hospital of Fujian Medical University

Fuzhou, Fujian, China

The Second People's Hospital of Shenzhen

Shenzhen, Guangdong, China

The Second Hospital of Hebei Medical University

Shijiazhuang, Hebei, China

North China University of Science And Technology Affiliated Hospital

Tangshan, Hebei, China

Tangshan Gongren Hospital

Tangshan, Hebei, China

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, China

Wuhan Brain Hospital,General Hospital of The Yangtze River Shipping

Wuhan, Hubei, China

Union Hospital,Tongji Medical College,Huazhong University of Science and Technology

Wuhan, Hubei, China

Wuhan No.1 Hospital

Wuhan, Hubei, China

Renmin Hospital of Wuhan University

Wuhan, Hubei, China

Xiangya Hospital Central South University

Changsha, Hunan, China

Northern Jiangsu People's Hospital,Clinical Medical School,YangZhou University

Yangzhou, Jiangsu, China

General Hospital of Shenyang Military

Shengyang, Liaoning, China

The Second Hospital of Shanxi Medical University

Taiyuan, Shanxi, China

General Hospital of TISCO

Taiyuan, Shanxi, China

Taizhou First People's Hospital,Huangyan Hospital of Wenzhou Medical University

Taizhou, Zhejiang, China

The First Affiliated Hospital of Wenzhou Medical University

Wenzhou, Zhejiang, China

Wenzhou Hospital of integrated Chinese and Western medicine

Wenzhou, Zhejiang, 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

Daping Hospital,Third Military Medical University

Chongqing, , China

Renji Hospital,Shanghai Jiao Tong University School of Medicine

Shanghai, , China

Tianjin Huanhu Hospital

Tianjin, , China

Countries

China

References

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.

Reference Type: DERIVED

PMID: 32587571 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32052517 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31171523 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28381198 (View on PubMed)

Other Identifiers

81322019

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

D151100002015001

Identifier Type: -

Identifier Source: org_study_id