Trial in Subjects Undergoing Cardiac Catheterization With Planned Percutaneous Coronary Intervention With Stenting

Study Overview
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Brief Summary
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The purpose of this study is to provide information of the relative potency of prasugrel and clopidogrel on platelet function studies, inflammation, and myocyte necrosis in subjects undergoing elective percutaneous coronary intervention (PCI).

Official Title
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Protocol H7T-MC-TABL(a) PRasugrel IN Comparison to Clopidogrel for Inhibition of PLatelet Activation and AggrEgation (PRINCIPLE) - TIMI 44

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Clopidogrel
* Drug: Placebo for Prasugrel
* Drug: Placebo for Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects greater than or equal to 18 years of age undergoing cardiac catheterization with planned percutaneous coronary intervention (if coronary anatomy is suitable) for an indication of chest pain +/or anginal equivalent felt by the treating physician to be related to coronary ischemia. At least one of the following (a through c): Functional study (exercise, or pharmacologic) within the past 8 weeks consistent with ischemia as manifested by at least one of the following: A reversible defect on nuclear imaging. A reversible wall-motion abnormality by echocardiography. Horizontal or down-sloping ST-depressions greater than 1 mm on electrocardiogram (ECG) (if no imaging performed). Prior coronary revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)]. A cardiac catheterization with at least one coronary artery lesion amenable to PCI (not yet performed) within 14 days prior to enrollment. Exclusion Criteria: Known creatine kinase-myocardial bands (CK-MB)or cardiac troponin greater than the upper limit of normal at time of screening Planned PCI for acute myocardial infarction (MI) or planned PCI within 48 hours of fibrinolytic therapy for ST segment elevation myocardial infarction (STEMI) Have cardiogenic shock at the time of screening (systolic blood pressure 90 mm Hg associated with clinical evidence of end-organ hypoperfusion, or subjects requiring vasopressors to maintain systolic blood pressure over 90 mm Hg and associated with clinical evidence of end-organ hypoperfusion). Refractory ventricular arrhythmias Have New York Heart Association Class IV congestive heart failure

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel to Clopidogrel<br>One time oral loading dose (LD) of 60-mg Prasugrel and placebo matched to clopidogrel (plus oral enteric coated aspirin 325 mg to 500 mg is recommended) followed by 10-mg Prasugrel and placebo matched to clopidogrel taken orally once a day for 14 days. Patients cross-over to 150 mg clopidogrel and placebo matched to prasugrel taken orally once a day for the next 14 days. | Drug: Prasugrel<br>* Administered orally<br>* Other names: Efient;Drug: Clopidogrel<br>* Administered orally<br>Drug: Placebo for Prasugrel<br>* Administered orally<br>Drug: Placebo for Clopidogrel<br>* Administered orally<br>|
| Active Comparator: Clopidogrel to Prasugrel<br>One time oral LD of 600 mg clopidogrel and placebo matched to prasugrel (plus oral enteric coated aspirin 325 mg to 500 mg is recommended) followed by 150 mg clopidogrel and placebo matched to prasugrel taken orally once a day for 14 days. Patients cross-over to 10 mg prasugrel and placebo tablets matched to clopidogrel taken orally once a day for the next 14 days. | Drug: Prasugrel<br>* Administered orally<br>* Other names: Efient;Drug: Clopidogrel<br>* Administered orally<br>Drug: Placebo for Prasugrel<br>* Administered orally<br>Drug: Placebo for Clopidogrel<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibition of Platelet Aggregation (IPA) to 20 Micromolar (μM) Adenosine Diphosphate (ADP) at 6 Hours After the Loading Dose | IPA was defined as (1 - [maximal platelet aggregation(MPA) at 6 hours after study drug treatment]/[MPA before drug treatment]) x 100. | 6 hours after loading dose | 
| Inhibition of Platelet Aggregation to 20 μM Adenosine Diphosphate After 14 Days of Maintenance Dose Treatment | Measures IPA during maintenance dosing before and after cross-over for each therapy. IPA was defined as (1 - [maximal platelet aggregation(MPA) at 14 days after study drug treatment]/[MPA before drug treatment]) x 100. | after 14 days of maintenance dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibition of Platelet Aggregation to 20 μM Adenosine Diphosphate at 2 Hours After the Loading Dose | IPA was defined as (1 - [maximal platelet aggregation (MPA) at 2 hours after study drug treatment]/[MPA before drug treatment]) x 100. | 2 hours after loading dose | 
| Number of Participants With Non-Coronary Artery Bypass Graft (CABG) Thrombolysis in Myocardial Infarction (TIMI) Major or Minor Bleeding During the First Maintenance Dose Phase | Non-CABG-related TIMI major bleeding was any intracranial hemorrhage OR any clinically overt bleeding associated with a fall in hemoglobin >=5 gm/dL. Non-CABG-related TIMI minor bleeding was any clinically overt bleeding associated with a fall in hemoglobin >=3 gm/dL but <5 gm/dL. | after 14 days of treatment (before cross-over) | 
| Number of Participants With Non-Coronary Artery Bypass Graft (CABG) Thrombolysis in Myocardial Infarction (TIMI) Major or Minor Bleeding During the Crossover Maintenance Dose Phase | Non-CABG-related TIMI major bleeding was any intracranial hemorrhage OR any clinically overt bleeding associated with a fall in hemoglobin >=5 gm/dL. Non-CABG-related TIMI minor bleeding was any clinically overt bleeding associated with a fall in hemoglobin >=3 gm/dL but <5 gm/dL. | 14 days after cross-over | 
| Number of Participants With Major Adverse Cardiac Events (MACE) During the First Maintenance Dose Phase | Number of patients who met any of the following endpoints: cardiovascular death, myocardial infarction, stroke, subacute stent thrombosis, or urgent target vessel revascularization | after 14 days of treatment (before cross-over) | 
| Number of Participants With Major Adverse Cardiac Events During the Crossover Maintenance Dose Phase | Number of patients who met any of the following endpoints: cardiovascular death, myocardial infarction, stroke, subacute stent thrombosis, or urgent target vessel revascularization | 14 days after cross-over | 
| Number of Hyporesponsive Participants at 6 Hours After the Loading Dose | Number of patients with inhibition of platelet aggregation (IPA) with 20 uM adenosine diphosphate (ADP) <20% | 6 hours after loading dose | 
| Number of Hyporesponsive Participants at the End of the First Maintenance Dose Phase | Number of patients with inhibition of platelet aggregation (IPA) with 20 uM adenosine diphosphate (ADP) <20% | From loading dose to day 15 | 
| Number of Hyporesponsive Participants at the End of the Crossover Maintenance Dose Phase | Number of patients with inhibition of platelet aggregation (IPA) with 20 uM adenosine diphosphate (ADP) <20% | 14 days after cross-over | 
| Platelet Reactivity Index Percent (PRI%) Measured by Vasodilator-stimulated Phosphoprotein (VASP) at 2 Hours After the Loading Dose | VASP phosphorylation in response to prostaglandin E1 (PGE1) with and without ADP was determined by whole-blood flow cytometry and was expressed as a platelet reactivity index (PRI). PRI was defined as [(MFI(with PGE1) - MFI (with PGE1 and ADP))/MFI(with PGE1) x 100] where MFI is mean fluorescence index. A lower PRI indicates greater antiplatelet effect. | 2 hours after loading dose | 
| Platelet Reactivity Index Percent (PRI%) Measured by Vasodilator-stimulated Phosphoprotein (VASP) at 6 Hours After the Loading Dose | VASP phosphorylation in response to prostaglandin E1 (PGE1) with and without ADP was determined by whole-blood flow cytometry and was expressed as a platelet reactivity index (PRI). PRI was defined as [(MFI(with PGE1) - MFI (with PGE1 and ADP))/MFI(with PGE1) x 100] where MFI is mean fluorescence index. A lower PRI indicates greater antiplatelet effect. | 6 hours after loading dose | 
| Platelet Reactivity Index Percent (PRI%) Measured by Vasodilator-stimulated Phosphoprotein (VASP) 18 to 24 Hours After the Loading Dose | VASP phosphorylation in response to prostaglandin E1 (PGE1) with and without ADP was determined by whole-blood flow cytometry and was expressed as a platelet reactivity index (PRI). PRI was defined as [(MFI(with PGE1) - MFI (with PGE1 and ADP))/MFI(with PGE1) x 100] where MFI is mean flourescence index. A lower PRI indicates greater antiplatelet effect. | 18 to 24 hours after loading dose | 
| Platelet Reactivity Index Percent (PRI%) Measured by Vasodilator-stimulated Phosphoprotein (VASP) After 14 Days of Maintenance Dose Treatment | VASP phosphorylation in response to prostaglandin E1 (PGE1) with and without ADP was determined by whole-blood flow cytometry and was expressed as a platelet reactivity index (PRI). PRI was defined as [(MFI(with PGE1) - MFI (with PGE1 and ADP))/MFI(with PGE1) x 100] where MFI is mean fluorescence index. A lower PRI indicates greater antiplatelet effect. | after 14 days of maintenance dosing | 
| Myonecrosis Measure: Creatine Kinase-Myocardial Bands (CK-MB) at 6 Hours After the Loading Dose | Mean CK-MB at 6 hours after loading dose. CK-MB is a biomarker for myonecrosis | 6 hours after loading dose | 
| Myonecrosis Measure: Creatine Kinase-Myocardial Bands (CK-MB) 18 to 24 Hours After the Loading Dose | Mean CK-MB at 18-24 hours after loading dose. CK-MB is a biomarker for myonecrosis. | 18 to 24 hours after loading dose | 
| Myonecrosis Measure: Cardiac Troponin at 6 Hours After the Loading Dose | Mean troponin level at 6 hours after the loading dose. Troponin is a biomarker for myonecrosis. | 6 hours after loading dose | 
| Myonecrosis Measure: Cardiac Troponin 18 to 24 Hours After the Loading Dose | Mean troponin level at 18 to 24 hours after the loading dose. Troponin is a biomarker for myonecrosis. | 18 to 24 hours after loading dose |