The Effect on Blood Cells, Known as Platelets, Using Prasugrel vs Clopidogrel in Patients With the Heart Problem Acute Coronary Syndrome (ACS)

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, cross-over study to compare the pharmacodynamic response in subjects with Acute Coronary Syndrome receiving a 10-mg maintenance dose (MD) of prasugrel compared with a 150-mg maintenance dose of clopidogrel, following a 900-mg loading dose (LD) of clopidogrel.

Official Title
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A Randomized Double-Blind Cross-Over Study Comparing the Pharmacodynamic (PD)Response in Subjects With ACS Receiving 14 Days 10-mg Maintenance Dose (MD) Prasugrel vs 14 Days 150-mg MD Clopidogrel After Using a 900-mg Loading Dose (LD) of Clopidogrel to Reduce Ongoing Platelet Activation

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Present with acute coronary syndrome (ACS) and have planned treatment with a one-time 900-mg loading dose of commercially available clopidogrel (administered as a single or cumulative dose). Are between the ages of 18 and 85 years. Willing and able to sign informed consent. Exclusion Criteria: Have overt ST-segment elevation myocardial infarction (STEMI). Have cardiogenic shock. Have refractory ventricular arrhythmias. Have New York Heart Association (NYHA) Class IV congestive heart failure. Have severe and uncontrolled hypertension. Have active internal bleeding or history of bleeding diathesis. Have an increased risk of bleeding. Have history of cerebrovascular accidents. Have certain abnormal blood level values. Are currently receiving chemotherapy or radiation therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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<br>Open label lead-in one time dose of Clopidogrel 900 mg oral tablets (a single or cumulative dose) and 250 mg to 500 mg aspirin loading dose (LD), either orally or intravenously. Patients are then assigned to maintenance dose (MD) prasugrel 10 mg and two placebo tablets, matched to clopidogrel, and 100 mg aspirin, all taken orally once a day for 14 days. Patients cross-over to MD of clopidogrel two 75 mg tablets and one placebo matched to prasugrel and 100 mg aspirin, all taken orally once a day for the next 14 days. | Drug: Prasugrel<br>* Prasugrel 10-mg tablet taken orally as a daily maintenance dose for a 14-day treatment period.<br>* Other names: Efient;|
| Active Comparator: Clopidogrel<br>Open label lead-in one time dose of Clopidogrel 900 mg oral tablets (a single or cumulative dose) and 250 mg to 500 mg aspirin loading dose (LD), either orally or intravenously. Patients are then assigned to maintenance dose (MD) Clopidogrel two 75 mg and one placebo tablet, matched to prasugrel, and 100 mg aspirin, all taken orally once a day for 14 days. Patients cross-over to MD of prasugrel one 10 mg tablet and two placebo tablets matched to clopidogrel and 100 mg aspirin, all taken orally once a day for the next 14 days. | Drug: Clopidogrel<br>* Clopidogrel two 75-mg tablets taken orally as a daily maintenance dose for a 14-day treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Platelet Aggregation (MPA) to 20 Micromolar (μM) Adenosine Diphosphate (ADP) | Maximum platelet aggregation (MPA) to 20 μM adenosine diphosphate (ADP) was assessed by light transmission aggregometry (LTA). | 14 days after maintenance dose (MD) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MPA to 5 μM ADP | Maximum platelet aggregation to 5 μM ADP was assessed by LTA. | 14 days after maintenance dose (MD) | 
| Mean Residual Platelet Aggregation (RPA) to 20 µM ADP | Residual platelet aggregation is the percentage (%) aggregation value as measured by LTA at 6 minutes after the addition of ADP. | 14 days after maintenance dose (MD) | 
| Mean Residual Platelet Aggregation (RPA) to 5 µM ADP | Residual platelet aggregation is the percentage (%) aggregation value as measured by LTA at 6 minutes after the addition of ADP. | 14 days after maintenance dose (MD) | 
| Inhibition Platelet Aggregation (IPA) to 20 μM ADP | IPA is calculated as a percent decrease of MPA from baseline using the following formula: ([MPA at baseline - MPA at time of postbaseline] / MPA at baseline) x 100% | 14 days after maintenance dose (MD) | 
| Inhibition Platelet Aggregation (IPA) to 5 μM ADP | IPA is calculated as a percent decrease of MPA from baseline using the following formula: ([MPA at baseline - MPA at time of postbaseline] / MPA at baseline) x 100% | 14 days after maintenance dose (MD) | 
| Inhibition of Residual Platelet Aggregation (IRPA) to 20 μM ADP | IRPA is calculated as a percent decrease of RPA from baseline using the following formula: ([RPA at baseline - RPA at time of postbaseline] / RPA at baseline) x 100% | 14 days after maintenance dose (MD) | 
| Inhibition of Residual Platelet Aggregation (IRPA) to 5 μM ADP | IRPA is calculated as a percent decrease of RPA from baseline using the following formula: ([RPA at baseline - RPA at time of postbaseline] / RPA at baseline) x 100% | 14 days after maintenance dose (MD) | 
| Platelet Reactivity Index (PRI) | Platelet Reactivity Index percentage was assessed by Vasodilator-stimulated phosphoprotein (VASP). PRI percent (%) was calculated using the median fluorescence intensity (MFI) of samples included with prostaglandin E1 (PGE1) and ADP, according to the following formula: PRI%=[(MFI(PGE1)-MFI(PGE1 + ADP)/MFI(PGE1)]x100 Lower PRI% values indicate greater P2Y12 receptor blockade. | 14 days after maintenance dose (MD) | 
| P2Y12 Reaction Units (PRU) | P2Y12 Reaction Units (PRU) assessed by Accumetrics Verify NowTM P2Y12. PRU represents the rate and extent of adenosine (ADP)-stimulated platelet aggregation. Lower values indicate greater P2Y12 platelet inhibition. | 14 days after maintenance dose (MD) | 
| Poor Responder of MPA to 20 μM ADP Following Maintenance Dose (MD) | Poor responder is defined as MPA to 20 μM ADP >75th percentile of the value at 6-18 hours post-clopidogrel LD. | 14 days after maintenance dose (MD) | 
| Change in MPA to 20 μM ADP From Baseline to 6-18 Hrs Post Loading Dose (LD) | Maximum platelet aggregation to 20 μM ADP was assessed by LTA. | Baseline to 6-18 hrs post loading dose (LD) | 
| Change in MPA to 20 μM ADP From 6-18 Hrs Post Loading Dose (LD) to 14 Days After the First Maintenance Dose (MD) | Maximum platelet aggregation to 20 μM ADP was assessed by LTA. | 6-18 hrs post loading dose (LD) to 14 days after the first maintenance dose (MD) | 
| MPA to 20 μM ADP at 14 Days After the First Maintenance Dose (MD) | Maximum platelet aggregation to 20 μM ADP was assessed by LTA. | 14 days after the first maintenance dose (MD) | 
| MPA to 20 μM ADP at 14 Days After the Second Maintenance Dose (MD) | Maximum platelet aggregation to 20 μM ADP was assessed by LTA. | 14 days after the second maintenance dose (MD) | 
| Number of Participants With Bleeding Events According to Thrombolysis in Myocardial Infarction Study Group (TIMI) Criteria | Bleeding events will be classified as Major Bleeding, Minor Bleeding, or Insignificant Bleeding according to the TIMI criteria. Major bleeding: any intracranial hemorrhage (ICH) OR any clinically overt bleeding (including bleeding evident on imaging studies) associated with a fall in hemoglobin (Hgb) of ≥5 gm/dL from baseline. Minor Bleeding: any clinically overt bleeding associated with a fall in Hgb of ≥3 grams/deciliter (gm/dL) but <5 gm/dL from baseline. Insignificant bleeding: any bleeding event that does not meet criteria for a Major or Minor bleed. | 14 days after maintenance dose (MD) | 
| Number of Participants With Bleeding Events According to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) | Bleeding events will be classified according to the GUSTO definitions as follows: Severe or Life-Threatening Bleeding: any ICH OR any bleeding event resulting in substantial hemodynamic compromise requiring treatment. Moderate Bleeding: any bleeding event resulting in the need for transfusion. Minor bleeding: any other bleeding event that does not require transfusion or cause hemodynamic compromise. | 14 days after maintenance dose (MD) | 
| Correlation of MPA to 20 μM ADP and PRU | Pearson-correlation estimated between MPA to 20 μM ADP and Accumetrics VerifyNowTM P2Y12 PRU | Baseline through 29 days of treatment |