A Comparison of Antiplatelet Therapies in Asian Subjects With Acute Coronary Syndrome

Study Overview
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Brief Summary
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The study will compare the safety and efficacy of prasugrel, administered at different doses with clopidogrel in the treatment of Asian participants with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention.

Official Title
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A Comparison of Platelet Inhibition Following Prasugrel or Clopidogrel Administration in Asian Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention

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: A person who has been diagnosed with acute coronary syndrome (ACS) and is to undergo a percutaneous coronary intervention (PCI) A person who is of East or Southeast Asian descent A person who is of the legal age of 18 (or age 21 in Singapore) and is mentally competent to provide a signed written informed consent before entering the study If a woman is of childbearing potential, she must test negative for pregnancy and agree to use a reliable method of birth control Exclusion Criteria: A person who has a severe cardiovascular condition such as cardiogenic shock at the time of randomization, ventricular arrhythmias or congestive heart failure A person who is at an increased risk of bleeding (e.g. active internal bleeding, history of bleeding disorder, recent fibrinolytic therapy before randomization into the study) A person who has prior history of any one of the following: ischemic or hemorrhagic stroke; intracranial neoplasm, arteriovenous malformation, or aneurysm; prior history of transient ischemic attack (TIA) A person who needs to take other antiplatelet therapy other than Aspirin for the duration of the study A person who receives daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX2) inhibitors that cannot be discontinued A person who has a severe liver disease, such as cirrhosis A person who has a condition such as alcoholism, mental illness, or drug dependence

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel 60/10 Primary<br>Loading dose 60 mg followed by maintenance dose 10 mg/day | Drug: Prasugrel<br>* Oral, daily, 90 days<br>* Other names: CS-747;|
| Experimental: Prasugrel 30/7.5 Primary<br>Loading dose 30 mg followed by maintenance dose 7.5 mg/day | Drug: Prasugrel<br>* Oral, daily, 90 days<br>* Other names: CS-747;|
| Experimental: Prasugrel 30/5 Primary<br>Loading dose 30 mg followed by maintenance dose 5 mg/day | Drug: Prasugrel<br>* Oral, daily, 90 days<br>* Other names: CS-747;|
| Active Comparator: Clopidogrel 300/75 Primary<br>Loading dose 300 mg followed by maintenance dose 75 mg/day | Drug: Clopidogrel<br>* Oral, daily, 90 days<br>* Other names: Plavix;|
| Experimental: Prasugrel 30/5 Low Weight/Elderly<br>Loading dose 30 mg followed by maintenance dose 5 mg/day | Drug: Prasugrel<br>* Oral, daily, 90 days<br>* Other names: CS-747;|
| Active Comparator: Clopidogrel 300/75 Low Weight/Elderly<br>Loading dose 300 mg followed by maintenance dose 75 mg/day | Drug: Clopidogrel<br>* Oral, daily, 90 days<br>* Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adenosine Diphosphate (ADP)-Induced P2Y12 Receptor-mediated Platelet Aggregation (P2Y12 Reaction Units; PRU) Using the Accumetrics VerifyNow (VN) P2Y12 Assay at 4 Hours Post-Loading Dose (LD) in Primary Cohort (≥60 kg and <75 Years) | ADP-induced PRU represents the rate and extent of ADP-stimulated platelet aggregation and serves as a biomarker of clinical efficacy, with lower values indicating greater P2Y12 platelet inhibition. Observed PRU values are presented with statistical comparisons of difference in least squares mean (LS mean) PRU values between prasugrel and clopidogrel. Efficacy analyses are analyzed and presented separately for the LD and maintenance dose (MD) phase. | At 4 hours following LD administration | 
| Adenosine Diphosphate (ADP)-Induced P2Y12 Reaction Units (PRU) Using the Accumetrics VerifyNow (VN) P2Y12 Assay at 30 Days During Maintenance Dose (MD) Administration in Primary Cohort | Efficacy analyses are analyzed and presented separately for the loading dose (LD) and MD phase. This primary outcome analysis compares PRU for the 3 prasugrel MDs (10 mg, 7.5 mg, and 5 mg) with the clopidogrel 75-mg MD at 30 days post-MD in the primary cohort (participants who weighed ≥60 kg and were <75 years). ADP-induced PRU serves as a biomarker of clinical efficacy, with lower values indicating greater P2Y12 platelet inhibition. Observed PRU values are presented with statistical comparisons of LS mean difference between prasugrel and clopidogrel. | At 30 days during MD therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adenosine Diphosphate (ADP)-Induced P2Y12 Reaction Units (PRU) Using the Accumetrics VerifyNow (VN) P2Y12 Assay at 30 Minutes, 2 and 4 Hours Post-Loading Dose (LD) in Primary (≥60 kg and <75 Years) and Low Weight/Elderly (<60 kg or ≥75 Years) Cohorts. | Efficacy analyses analyzed and presented separately for LD and maintenance dose (MD) phase. Analysis compares PRU for prasugrel LDs (30 mg and 60 mg) with clopidogrel 300-mg LD at 30 minutes post-LD. Data for Primary Cohort at 4 hours post-LD, already presented in first Primary Outcome Measure, are also presented here. ADP-induced PRU serves as biomarker of clinical efficacy, with lower values indicating greater P2Y12 platelet inhibition. Observed PRU values presented with statistical comparisons of least-squares mean (LS mean) difference between prasugrel and clopidogrel. | At 30 minutes, 2 hours, and 4 hours following LD administration | 
| Adenosine Diphosphate (ADP)-Induced P2Y12 Reaction Units (PRU) Using the Accumetrics VerifyNow (VN) P2Y12 Assay at During Maintenance Dose (MD) Phase at 30 Days and 90 Days in Primary Cohort and Low Weight/Elderly Cohort | Efficacy analyses analyzed and presented separately for loading dose (LD) and MD phase. Analysis compares PRU for 3 prasugrel MDs (10 mg, 7.5 mg, and 5 mg) with clopidogrel 75-mg MD at 30 days post-MD. Data for Primary Cohort at 30 days post-LD, already presented in second Primary Outcome Measure, are also presented here. ADP-induced PRU serves as a biomarker of clinical efficacy, with lower values indicating greater P2Y12 platelet inhibition. Observed PRU values are presented with statistical comparisons of least squares (LS) mean difference between prasugrel and clopidogrel. | At 30 Days and 90 days during MD therapy | 
| Percent Inhibition of Adenosine Diphosphate (ADP)-Induced P2Y12 Reaction Units (PRU) at 30 Minutes, 2 Hours, and 4 Hours Post-Loading Dose (LD) in Primary in Primary Cohort and Low Weight/Elderly Cohort | A higher percentage (percent inhibition least squares mean [LS mean]) represents greater platelet inhibition. | 30 minutes, 2 hours, and 4 hours following LD administration | 
| Percent Inhibition of Adenosine Diphosphate (ADP)-Induced P2Y12 Reaction Units (PRU) During the Maintenance Dose (MD) Phase at 30 Days and 90 Days in Primary Cohort and Low Weight/Elderly Cohort | A higher percentage (percent inhibition least squares mean [LS mean]) represents greater platelet inhibition. | 30 days and at 90 days during MD therapy | 
| Summary of Myocardial Infarction (MI), Stroke, Stent Thrombosis and Urgent Target Vessel Revascularization (UTVR) in Primary Cohort and Low Weight/Elderly Cohort | Nonfatal MI: American College of Cardiology (ACC) definition Nonfatal stroke: rapid onset of new, persistent neurologic deficit lasting >24 hours; classified as either ischemic or hemorrhagic based on imaging data, if available, or uncertain cause if imaging data was not available. Stent thrombosis: defined as definite, probable, or possible, based on Academic Research Consortium definitions. UTVR: percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) for recurrent ischemia. Revascularization must have included the vessel(s) dilated at the initial procedure | Randomization through end of study (90 days) | 
| Risk of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), or Non-fatal Stroke | Risk was defined as the number of participants with events of CV death, nonfatal MI, or nonfatal stroke. CV death: death caused by CV event or not clearly attributable to non-CV causes. Nonfatal MI: per adapted American College of Cardiology definition. Nonfatal stroke: rapid onset of new, persistent neurologic deficit lasting more than 24 hours; either ischemic or hemorrhagic based on imaging data, if available, or uncertain cause if imaging data was not available. As a consequence of the overall low number of reported clinical events, composite endpoints were not analyzed. | 30 days and 90 days | 
| Risk of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), or Urgent Target Vessel Revascularization (UTVR) | Risk was defined as the number of participants with events of CV death, nonfatal MI, or UTVR. UTVR: percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) for recurrent ischemia. Revascularization must have included the vessel(s) dilated at the initial procedure. As a consequence of the overall low number of reported clinical events, composite endpoints were not analyzed. | 30 days and 90 days | 
| Risk of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, or Recurrent Myocardial Ischemia Requiring Hospitalization | Risk was defined as the number of events of CV death, nonfatal MI, nonfatal stroke or recurrent myocardial ischemia requiring hospitalization. Recurrent myocardial ischemia requiring hospitalization: rehospitalization for symptoms of myocardial ischemia at rest with either new ST-segment deviation ≥1 mm, or performance of a coronary revascularization procedure percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) during the same hospital stay. As a consequence of the overall low number of reported clinical events, composite endpoints were not analyzed. | 30 days and 90 days | 
| Risk of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Urgent Target Vessel Revascularization (UTVR), or Recurrent Myocardial Ischemia Requiring Hospitalization (Analyzed Individually) | Risk was defined as the number of participants with events of CV death, nonfatal MI, nonfatal stroke, UTVR, or recurrent myocardial ischemia requiring hospitalization. | 30 days and 90 days | 
| Risk of Definite or Probable Stent Thrombosis Per ARC (Academic Research Consortium) Definition | Risk was defined as the number of participants with events of definite or probable stent thrombosis. As a consequence of the overall low number of reported clinical events, composite endpoints were not analyzed. | 30 days and 90 days | 
| Risk of Definite, Probable, or Possible Stent Thrombosis Per Academic Research Consortium (ARC) Definition | Risk was defined as the number of participants with events of definite, probable, or possible stent thrombosis. As a consequence of the overall low number of reported clinical events, composite endpoints were not analyzed. | 90 days | 
| Risk of All-cause Death in Primary Cohort and Low Weight/Elderly Cohort | Risk was defined as the number of participants with events of all-cause death. | Randomization through end of study (90 days) | 
| Incidence of Non-coronary Artery Bypass Graft (CABG) Related Thrombolysis in Myocardial Infarction (TIMI) Life-threatening (a Subset of Non-CABG-related TIMI Major Bleeding), Major, Minor, and Minimal Bleeding | Bleeding events were classified and analyzed in accordance with the TIMI criteria definitions. Major bleeding: any intracranial hemorrhage (ICR) OR any clinically overt bleeding (including bleeding evident on imaging studies) associated with a fall in hemoglobin (Hgb) of ≥5 grams/deciliter (gm/dL) from baseline. Minor bleeding: any clinically overt bleeding associated with a fall in Hgb of ≥3 but <5 gm/dL from baseline. Insignificant bleeding: any bleeding event that does not meet criteria for a Major or Minor bleed. | Randomization through end of study (90 days) | 
| Incidence of CABG-related TIMI Major or Minor Bleeding. |  | Randomization through end of study (90 days) | 
| Inpatient Healthcare Resource Utilization | Healthcare resource utilization data were modeled from historical analyses to determine initial hospitalization costs, total 30-day medical care costs, and total 90-day medical care costs. | Initial hospitalization, 30 days, 90 days | 
| Genetic Variation Related to Drug Metabolism and Transport Substudy Result Summary | The primary hypothesis for the genetics substudy was that CYP2C19 genetic variation has a significant effect on pharmacodynamic (PD) response to clopidogrel but not on PD response to prasugrel per change in PRU as measured by the Accumetrics VerifyNow P2Y12 device. Participants were classified by CYP2C19 genotype into predicted metabolic phenotypes according to literature-based functional predictions. These classifications were clustered into 2 groups: extensive metabolizer (EM) and reduced metabolizer (RM). A higher value for change in PRU indicates a greater level of platelet inhibition. | Baseline to 4 hours post-loading dose (LD), 30 days and 90 days during maintenance dose (MD) phase | 
| Risk of CV Death, Nonfatal MI, Nonfatal Stroke, UTVR, or Recurrent Myocardial Ischemia Requiring Hospitalization (Analyzed Individually) | Risk of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Urgent Target Vessel Revascularization (UTVR), or Recurrent Myocardial Ischemia Requiring Hospitalization (Analyzed Individually) | 30 days and 90 days |