Platelet Reactivity in Acute Non-disabling Cerebrovascular Events "PRINCE"

Recruiting

Phase 2/3 Results N/A

Trial Description

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

Interventions

  • Ticagrelor and Acetylsalicylic acid Drug
    Other Names: BRILINTA; Aspirin
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Ticagrelor/ASA
    Description: Drugs: Ticagrelor and Acetylsalicylic acid.
  • Clopidogrel and Acetylsalicylic acid Drug
    Other Names: Plavix; Aspirin
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Clopidogrel/ASA
    Description: Drugs: Clopidogrel and Acetylsalicylic acid.

Trial Design

  • Allocation: Randomized
  • Masking: Single Blind (Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Efficacy Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure 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 No
Secondary HOPR at 90 days in subjects carrying genetic variants which affected Clopidogrel metabolism. 90 days No
Secondary New vascular events defined as any event of the following: Any stroke (ischemic or hemorrhage). 90 days, 6 months, 1 year No
Secondary New composite clinical vascular events (ischemic stroke/ hemorrhagic stroke/TIA/ myocardial infarction/ vascular death) as a cluster. 90 days, 6 months, 1 year No
Secondary High on-treatment platelet reactivity defined as PRU> 208 measured by VerifyNow® assay. 2hours, 24 hours, 7 days No
Secondary High on-treatment platelet reactivity defined as Aspirin reactivity unit (ARU)> 555 measured by VerifyNow® assay. 7 days No
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 No
Secondary Residual platelet reactivity defined as the value of PRU. 2hours, 24 hours, 7 days, 90 days No
Secondary Residual platelet reactivity defined as the value of Aspirin reaction unit (ARU). 7days No
Secondary Residual platelet reactivity defined as the value of MA-ADP. 7days, 90 days No
Secondary Residual platelet reactivity defined as the value of Maximum Amplitude- acetylsalicylic acid (MA-AA) measured by TEG. 7days No
Secondary Residual platelet reactivity change from baseline in PRU. 2hours, 24 hours, 7 days, 90 days No
Secondary Residual platelet reactivity change from baseline in ARU. 7 days No
Secondary The inhibition of platelet aggregation (IPA) measured by VerifyNow® assay. 2hours, 24 hours, 7 days, 90 days No
Secondary The TEG-platelet inhibition(TPI)measured by TEG. 7 days, 90 days No
Secondary Platelet inhibition change from baseline in IPA. 2hours, 24 hours, 7 days, 90 days No
Secondary Platelet inhibition change from baseline in TPI. 7 days, 90 days No
Secondary Residual platelet reactivity detected by AspirinWorks. 7days No
Secondary Residual platelet reactivity detected by PL Platelet Analyser (SINNOWA®). 7days, 90days No
Secondary Modified Rankin Scale score changes (continuous) and dichotomized at percentage with score 0-2 vs. 3-6. 90 days, 6 months, 1 year No
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 No
Secondary Further efficacy exploratory analysis:Quality of Life (The EuroQol-5D 3 level version[EQ-5D-3L]scale). 90 days, 6 months, 1 year No
Secondary Major bleed (PLATO definition), including fatal/life-threatening and other. 90 days, 6 months, 1 year Yes
Secondary Intracranial hemorrhagic events. 90 days, 6 months, 1 year Yes
Secondary Total mortality. 90 days, 6 months, 1 year Yes

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