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Platelet Reactivity in Acute Non-disabling Cerebrovascular Events (PRINCE)

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ClinicalTrials.gov Identifier: NCT02506140
Recruitment Status : Active, not recruiting
First Posted : July 23, 2015
Last Update Posted : December 13, 2017
Sponsor:
Collaborator:
Beijing Municipal Science & Technology Commission
Information provided by (Responsible Party):
yongjun wang, Ministry of Science and Technology of the People´s Republic of China

Tracking Information
First Submitted Date  ICMJE July 19, 2015
First Posted Date  ICMJE July 23, 2015
Last Update Posted Date December 13, 2017
Study Start Date  ICMJE August 2015
Actual Primary Completion Date June 10, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2015)
High on-treatment platelet reactivity (HOPR) defined as P2Y12 reaction unit (PRU)> 208 measured by VerifyNow® assay at 90 days [ Time Frame: 90 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02506140 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2015)
  • HOPR at 90 days in subjects carrying genetic variants which affected Clopidogrel metabolism. [ Time Frame: 90 days ]
    HOPR defined as P2Y12 reaction unit (PRU)> 208 measured by VerifyNow® assay
  • New vascular events defined as any event of the following: Any stroke (ischemic or hemorrhage). [ Time Frame: 90 days, 6 months, 1 year ]
    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.
  • New composite clinical vascular events (ischemic stroke/ hemorrhagic stroke/TIA/ myocardial infarction/ vascular death) as a cluster. [ Time Frame: 90 days, 6 months, 1 year ]
    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.
  • High on-treatment platelet reactivity defined as PRU> 208 measured by VerifyNow® assay. [ Time Frame: 2hours, 24 hours, 7 days ]
  • High on-treatment platelet reactivity defined as Aspirin reactivity unit (ARU)> 555 measured by VerifyNow® assay. [ Time Frame: 7 days ]
  • HOPR defined as Maximum Amplitude-adenosine diphosphate (MA-ADP)>47 measured by Thrombelastography Platelet Mapping Assay (TEG) using the inducer of adenosine diphosphate. [ Time Frame: 90 days ]
  • Residual platelet reactivity defined as the value of PRU. [ Time Frame: 2hours, 24 hours, 7 days, 90 days ]
  • Residual platelet reactivity defined as the value of Aspirin reaction unit (ARU). [ Time Frame: 7days ]
  • Residual platelet reactivity defined as the value of MA-ADP. [ Time Frame: 7days, 90 days ]
  • Residual platelet reactivity defined as the value of Maximum Amplitude- acetylsalicylic acid (MA-AA) measured by TEG. [ Time Frame: 7days ]
  • Residual platelet reactivity change from baseline in PRU. [ Time Frame: 2hours, 24 hours, 7 days, 90 days ]
  • Residual platelet reactivity change from baseline in ARU. [ Time Frame: 7 days ]
  • The inhibition of platelet aggregation (IPA) measured by VerifyNow® assay. [ Time Frame: 2hours, 24 hours, 7 days, 90 days ]
  • The TEG-platelet inhibition(TPI)measured by TEG. [ Time Frame: 7 days, 90 days ]
  • Platelet inhibition change from baseline in IPA. [ Time Frame: 2hours, 24 hours, 7 days, 90 days ]
  • Platelet inhibition change from baseline in TPI. [ Time Frame: 7 days, 90 days ]
  • Residual platelet reactivity detected by AspirinWorks. [ Time Frame: 7days ]
  • Residual platelet reactivity detected by PL Platelet Analyser (SINNOWA®). [ Time Frame: 7days, 90days ]
  • Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6. [ Time Frame: 90 days, 6 months, 1 year ]
  • Further efficacy exploratory analysis:Impairment (changes in NIHSS scores at 90 days, 6 months, 1 year follow-up) [ Time Frame: 90 days, 6 months, 1 year ]
  • Further efficacy exploratory analysis:Quality of Life (The EuroQol-5D 3 level version[EQ-5D-3L]scale). [ Time Frame: 90 days, 6 months, 1 year ]
  • Major bleed (PLATO definition), including fatal/life-threatening and other. [ Time Frame: 90 days, 6 months, 1 year ]
    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.
  • Intracranial hemorrhagic events. [ Time Frame: 90 days, 6 months, 1 year ]
    Intracranial hemorrhagic events is assessed by brain computed tomography (CT) or gradient recalled echo (GRE) T2 star weighted MRI.
  • Total mortality. [ Time Frame: 90 days, 6 months, 1 year ]
    All deaths reported post-randomization will be recorded and adjudicated. Deaths will be subclassified by the adjudication committee as cardiovascular or non-cardiovascular.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Platelet Reactivity in Acute Non-disabling Cerebrovascular Events
Official Title  ICMJE 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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Stroke
  • Ischemic Attack, Transient
Intervention  ICMJE
  • 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.
    Other Names:
    • BRILINTA
    • Aspirin
  • 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.
    Other Names:
    • Plavix
    • Aspirin
Study Arms  ICMJE
  • Experimental: Ticagrelor/ASA
    Drugs: Ticagrelor and Acetylsalicylic acid.
    Intervention: Drug: Ticagrelor and Acetylsalicylic acid
  • Active Comparator: Clopidogrel/ASA
    Drugs: Clopidogrel and Acetylsalicylic acid.
    Intervention: Drug: Clopidogrel and Acetylsalicylic acid
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 11, 2017)
675
Original Estimated Enrollment  ICMJE
 (submitted: July 22, 2015)
952
Estimated Study Completion Date  ICMJE March 10, 2018
Actual Primary Completion Date June 10, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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%
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02506140
Other Study ID Numbers  ICMJE D151100002015001
81322019 ( Other Grant/Funding Number: National Natural Science Foundation of China )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party yongjun wang, Ministry of Science and Technology of the People´s Republic of China
Study Sponsor  ICMJE Ministry of Science and Technology of the People´s Republic of China
Collaborators  ICMJE Beijing Municipal Science & Technology Commission
Investigators  ICMJE Not Provided
PRS Account Ministry of Science and Technology of the People´s Republic of China
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP