Pharmacodynamic Evaluation of Switching From Ticagrelor to Prasugrel in Subjects With Stable Coronary Artery Disease

Study Overview
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Brief Summary
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This is a Phase 4, multicenter, open-label (blinded Pharmacodynamic PD results), randomized, 3-arm, parallel-design study of subjects with stable Coronary Artery Disease CAD. This study will compare the PD effect of prasugrel 10 mg QD (once-daily) maintenance dose with ticagrelor 90 mg BID (twice daily) maintenance dose in subjects with stable CAD who have previously received ticagrelor loading does (LD) and maintenance dose (MD)..

Official Title
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A Pharmacodynamic Evaluation of Switching From Ticagrelor to Prasugrel in Subjects With Stable Coronary Artery Disease: 2nd Switching Antiplatelet Agents

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Prasugrel Loading Dose
* Drug: Prasugrel Maintenance Dose
* Drug: Ticagrelor Maintenance Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female; age >= 18 and < 75 years Weight >= 60 kg Receiving low dose ASA (75 mg to 150 mg daily) for at least 7 days at the time of Visit 1 and able to continue the same regimen throughout the study Stable CAD. CAD is defined as any of the following: History of a positive stress test Previous coronary revascularization including percutaneous coronary intervention (PCI), stent, or coronary artery bypass graft (CABG) Angiographic demonstration of CAD (at least 1 lesion >= 50 percent) Presence of at least moderate plaque by computed tomography (CT) angiography Electron beam CT coronary artery calcification score >= 100 Agatston units If female, may be enrolled if One of the following 3 criteria are met: Had a hysterectomy or tubal ligation at least 6 months prior to signing the informed consent form (ICF) Post-menopausal for at least 1 year If of childbearing potential, will practice 1 of the following methods of birth control throughout the study: oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide; or female condom plus spermicide. Methods of contraception that are not acceptable are partner's use of condoms or partner's vasectomy Able and willing to provide written informed consent before entering the study Exclusion Criteria: Have a defined need for adenosine diphosphate (ADP)-receptor inhibitor therapy, such as any of the following (or any other condition that in the Investigator's judgment would require such therapy): Within =< 12 months of an acute coronary syndrome (ACS) event (unstable angina [UA], non-ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]) regardless of initial treatment (that is, invasive versus noninvasive) Subjects who underwent angioplasty within 12 months including bare-metal stent and/or a drug-eluting stent Had any stent placed in an unprotected left main coronary artery or in the last patent artery within the last 12 months Received thienopyridine therapy within 30 days of study entry Plan to undergo coronary revascularization at any time during the trial Presence or history of any of the following: ischemic or hemorrhagic stroke; transient ischemic attack (TIA); intracranial neoplasm; arteriovenous malformation, or aneurysm; intracranial hemorrhage; head trauma (within 3 months of study entry) History of refractory ventricular arrhythmias with an increased risk of bradycardic events (eg, subjects without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree atrioventricular (AV) block or bradycardic-related syncope) History or evidence of congestive heart failure (New York Heart Association Class III or above =< 6 months before screening Severe hepatic impairment History of uric acid nephropathy Uncontrolled hypertension, or systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at screening Severely impaired renal function (glomerular filtration rate < 30 mL/minute) or on dialysis At risk for bleeding Taking prohibited medications

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel Maintenance Dose<br>Prasugrel 10 mg QD MD | Drug: Prasugrel Maintenance Dose<br>* 10mg maintenance dose, given as one 10mg film coated tablet<br>* Other names: Effient;|
| Active Comparator: Ticagrelor Maintenance Dose<br>Ticagrelor 90 mg twice-daily (BID) MD | Drug: Ticagrelor Maintenance Dose<br>* one 90mg film coated tablet<br>* Other names: Brilinta;|
| Experimental: Prasugrel Loading Dose<br>Prasugrel 60mg Loading Dose (LD), followed by prasugrel 10mg once-daily (QD) Maintenance Dose (MD) | Drug: Prasugrel Loading Dose<br>* 60mg given as six 10mg film coated tablets<br>* Other names: Effient;Drug: Prasugrel Maintenance Dose<br>* 10mg maintenance dose, given as one 10mg film coated tablet<br>* Other names: Effient;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P2Y12 Reaction Units | P2Y12 Reaction Units (PRU) measured by VerifyNow P2Y12 assay VerifyNow P2Y12 assay, developed by Accumetrics, Inc. (San Diego, CA, USA), has been approved by the FDA to assess clopidogrel response using whole blood in a point-of-care testing fashion. Platelet aggregation with this system is defined by PRU, with a higher PRU indicative of greater platelet aggregation, and a lower PRU indicative of inhibition. | 7 days after first randomized dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P2Y12 Reaction Units | P2Y12 Reaction Units (PRU) measured by VerifyNow P2Y12 assay measured at 2, 4, 24, 48 hours after first randomized study treatment | 2, 4, 24, 48 hours after first randomized dose | 
| Platelet Reactivity Index | Platelet Reactivity Index (PRI) by the Vasodilator-Stimulated Phosphoprotein(VASP) assay 2, 4, 24, 48 hours and 7 days after first randomized study treatment. The VASP assay is an indirect, but relatively specific measure of inhibition of P2Y12-induced platelet activation. The assay quantifies the level of phosphorylation of the intracellular protein VASP, which undergoes phosphorylation when platelet P2Y12 receptors are blocked. The level of VASP phosphorylation, expressed as the PRI, represents the percentage inhibition relative to an assay baseline/maximal P2Y12-independent platelet aggregation. | 2, 4, 24, 48 hours, 7 days after first randomized dose | 
| PRU Percent Inhibition (Device-reported) | PRU VerifyNow P2Y12 assay device-reported percent inhibition 2, 4, 24, and 48 hours, and 7 days after first randomized study treatment VerifyNow P2Y12 assay, developed by Accumetrics, Inc. (San Diego, CA, USA), has been approved by the FDA to assess clopidogrel response using whole blood in a point-of-care testing fashion. The percent inhibition reported by VerifyNow device represents the percentage inhibition relative to maximal P2Y12-independent platelet aggregation achieved with the same sample in the presence of the iso-thrombin receptor activating peptide. | 2, 4, 24, 48 hours, 7 days after first randomized dose | 
| PRU Percent Inhibition (Calculated) | Analysis of Mean Calculated Percent Inhibition by time point Calculated percent inhibition at time point t is defined as: 100 × (baseline PRU - PRUt)/baseline PRU where baseline PRU is the VerifyNow PRU value at pre-run-in baseline and PRUt is the VerifyNow PRU value at time t. | 2, 4, 24, 48 hours, 7 days after first randomized dose | 
| Percentage of Subjects With High On-treatment Platelet Reactivity | Percentage of subjects with High on-treatment Platelet Reactivity (HPR) defined as a) >= 208 PRU and b) >= 230 PRU by the VerifyNow P2Y12 assay and c) >50% PRI by the VASP assay, 2, 4, 24, and 48 hours and 7 days after first randomized study treatment. A poor response of the platelets to drug, called High Residual Platelet Reactivity (HRPR), has been incriminated to account for a recurrence of ischemic events | 2, 4, 24, 48 hours, 7 days after first randomized dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAD, prasugrel, ticagrelor, antiplatelet, thienopyridine, P2Y12 Inhibitors