Ticagrelor Administered as Standard Tablet or Orodispersible Formulation

Study Overview
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Brief Summary
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Randomized clinical study evaluating superiority in platelet inhibition after administration of Ticagrelor 180 mg loading dose as an orodispersible formulation versus traditional coated tablets in patients admitted for ST elevation myocardial infarction or very high-risk non-ST elevation myocardial infarction.

Detailed Description
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Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for patients with acute ST-segment elevation myocardial infarction (STEMI). Additional antithrombotic therapy prior or during intervention plays an important role in the short- and long-term outcomes after PPCI. Oral antiplatelet therapy including a platelet P2Y12 receptor inhibitors is a cornerstone of antithrombotic treatment in patients with acute coronary syndromes. Prasugrel and Ticagrelor have been shown to be superior to Clopidogrel in patients with STEMI in reduction of ischemic complication without any increase in the bleeding risk and with a significant reduction in the stent thrombosis rate. Nevertheless, in STEMI patients, pharmacodynamic studies showed prasugrel and ticagrelor oral loading dose (LD) provided a suboptimal platelet inhibition in the first hours after LD, and at least 4 hours are required to achieve and effective platelet aggregation inhibition in the majority of patients, in part due to slowed gut motility caused by morphine use. Orodispersible tablet (ODT) is a different tablet formulation that disperses upon contact with the moist mucosal surfaces of the oral cavity and quickly release its components before swallowing; thus local drug dissolution and absorption as well as onset of clinical effect can be obtained conveniently easily and quickly by bypassing gastrointestinal tract. Recently, Ticagrelor 90 mg ODT has become available and bioequivalence studies on healthy volunteers documented its effectiveness with consequent approval by European Medicine Agency of this formulation which is currently available on the market. Thus, the aim of the present study is to evaluate the superiority in platelet inhibition with 180 mg Ticagrelor loading dose (LD) administered as ODTs as compared with standard formulation, among patients with STEMI or very high-risk NSTEMI undergoing immediate PCI. Primary objective consists in evaluating platelet reactivity 1 hour after Ticagrelor loading dose by VerifyNow test.

Official Title
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Ticagrelor Administered as Standard Tablet or orodispersiblE foRmulation

Conditions
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ST Elevation Myocardial Infarction, NSTEMI - Non-ST Segment Elevation MI

Intervention / Treatment
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* Drug: Ticagrelor orodispersible tablets
* Drug: Ticagrelor standard tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients presenting within 12 hours from the onset of symptoms with STEMI or very high-risk NSTEMI referred for immediate (< 2 hours) angiography. Very high-risk NSTEMI patients include patients with haemodynamic instability or cardiogenic shock, heart failure, life-threatening arrhythmias or resuscitated cardiac arrest, intermittent ST-segment elevation, or ongoing chest pain. Informed, written consent Male or female patients, aged ≥ 18 years old Exclusion Criteria: Age < 18 years Active bleeding; bleeding diathesis; coagulopathy History of gastrointestinal or genitourinary bleeding <2 months Major surgery in the last 6 weeks History of intracranial bleeding or structural abnormalities Suspected aortic dissection Administration in the week before the index event of clopidogrel, ticlopidine, prasugrel, ticagrelor, thrombolytics, bivalirudin, low-molecular weight heparin or fondaparinux. Concomitant oral or IV therapy with strong CYP3A inhibitors or strong CYP3A inducers, CYP3A with narrow therapeutic window Known relevant hematological deviations: Hb <10 g/dl, Thromb. <100x10^9/l Use of warfarin or new oral anticoagulant derivatives within the last 7 days Known severe liver disease, severe renal failure Allergy or hypersensitivity to ticagrelor or any of the excipients. Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Comparison of platelet inhibition at different timepoints between 65 patients in the treatment arm (receiving orodispersible formulation of ticagrelor loading dose) versus 65 patients in the control arm (receiving standard coated formulation of ticagrelor loading dose). Randomization will be further stratified according to morphine use.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor orodispersible tablets<br>STEMI or very high-risk NSTEMI patients undergoing primary PCI and receiving Ticagrelor 180 mg loading dose as orodispersible tablets. Intervention: administration of Ticagrelor 180 mg loading dose as orodispersible tablets. | Drug: Ticagrelor orodispersible tablets<br>* Ticagrelor loading dose (180 mg) given as two orodispersible tablets (each of 90 mg), to be dispersed in saliva.<br>|
| Active Comparator: Ticagrelor standard tablets<br>STEMI or very high-risk NSTEMI patients undergoing primary PCI and receiving Ticagrelor 180 mg loading dose as standard coated tablets. Intervention: administration of Ticagrelor 180 mg loading dose as standard coated pills. | Drug: Ticagrelor standard tablets<br>* Ticagrelor loading dose (180 mg) given as two standard coated tablets (each of 90 mg) to be swallowed with water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Platelet Inhibition | Platelet reactivity will be measured by VerifyNow test 1 hour after Ticagrelor loading dose (LD) administered as orodispersible tablets as compared with standard formulation in 130 patients with STEMI or very high-risk NSTEMI undergoing immediate PCI. The VerifyNow PRU Test is designed to measure P2Y12 receptor blockade. Results of the PRU Tests are reported as P2Y12 Reaction Units (PRU). PRU measures the extent of platelet aggregation in the presence of a P2Y12 inhibitor. Lower PRU levels are associated with expected antiplatelet effect. | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients With Insufficient Antiaggregation | The percent of patients with a high residual platelet reactivity (PRU > 208 by VerifyNow test), thus not adequately antiaggregated, 1 hour after Ticagrelor LD. | 1 hour | 
| Number of Participants With Residual Platelet Reactivity at Various Timepoints | Residual platelet reactivity (PRU) at 2, 4 and 6 hours measured by VerifyNow test to assess antiplatelet effect of P2Y12 inhibitors | 2, 4 and 6 hours | 
| Number of Participants With Clinically Relevant Bleeding Events | Actionable bleeding events across the two different regimens of Ticagrelor administration, requiring diagnostic studies, hospitalization, or treatment by a health care professional (BARC type 2 or higher) | 30 days |