The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease

Study Overview
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Brief Summary
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This study is being conducted to determine if smoking will influence the platelet aggregation inhibition ability of clopidogrel and prasugrel. It will also determine if smoking has any effect on the plasma concentrations of the active metabolite of prasugrel and the active and inactive metabolites of clopidogrel. The primary hypothesis is that smoking status will influence the antiplatelet effects and active metabolite concentrations of clopidogrel but will have no impact on prasugrel's antiplatelet effects or active metabolite concentrations.

Detailed Description
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Subjects will be stratified according to smoking status prior to being randomized to 1 of the 2 treatment sequences: prasugrel 10 mg daily for 10 days followed by clopidogrel 75 mg daily for 10 days or clopidogrel 75 mg daily for 10 days followed by prasugrel 10 mg daily for 10 days. There will be a 14-day Washout Period between Active Treatment Period 1 (when subjects receive the first drug of the sequence) and the second Active Treatment Period 2 (Period 3) (when subjects receive the second drug of the sequence). All subjects will remain on the same dose of aspirin from baseline throughout the study.

Official Title
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The Influence of Smoking Status on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Aspirin-treated Subjects With Stable Coronary Artery Disease

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects > or = 18 years and <75 years of age; Weight > or = 60 kg; On aspirin therapy (81 mg to 325 mg daily) at the time of screening and able to maintain a consistent aspirin dosing regimen from the baseline visit through the final study visit; Subjects who do not have contraindications for a thienopyridine (ie, prasugrel, clopidogrel, or ticlopidine) and have a history of stable atherosclerosis represented by CAD, defined as any of the following: Chronic stable angina; Documented prior ACS event > or = 30 days before screening and not currently prescribed or currently on thienopyridine therapy; Previous coronary revascularization including percutaneous transluminal coronary angioplasty, stent, or coronary artery bypass graft; Coronary Artery Disease (> or = 40% obstruction) in at least one coronary vessel after angiography; Documented history of positive stress test; or High coronary artery calcium score (> or = 90th percentile for age and gender) determined by cardiac computed tomography scan; Current smokers who smoke > or = ½ pack per day of cigarettes with a NicAlert™ level of 6; Non-smokers with a NicAlert level of 0, 1, or 2; Female subjects who meet one of the following: Women of childbearing potential with a negative serum pregnancy test at screening, who are not breastfeeding, do not plan to become pregnant during the study, and agree to use an approved method of birth control during the study. Approved methods of birth control are intrauterine device, diaphragm plus spermicide, or female condom plus spermicide. Abstinence, partner's use of condoms, partner's vasectomy, and hormonal contraceptives are NOT acceptable methods of contraception; Women who have been postmenopausal for at least 1 year or have had a hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation at least 6 months prior to signing the Informed Consent Form (ICF); and Subjects with a competent mental condition to provide written informed consent before entering the study. Exclusion Criteria: Subjects who received a bare metal stent and/or a drug-eluting stent within the last 12 months; Subjects who have had an angiogram < or = 7 days before randomization; Any other formal indication for the use of a thienopyridine; Subjects with a history of refractory ventricular arrhythmias; Subjects with a history of an implantable defibrillator device; Subjects with a history or evidence of congestive heart failure (New York Heart Association Class III or above) within 6 months prior to screening; Subjects with significant hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) at either the time of screening or baseline assessment; Bleeding risk exclusion criteria: Any known contraindication to treatment with an anticoagulant or antiplatelet agent; Prior history or clinical suspicion of cerebral vascular malformations, intracranial tumor, transient ischemic attack, or stroke, or recent history (within 3 months) of head trauma; Prior history or presence of significant bleeding disorders (eg, hematemesis, melena, severe or recurrent epistaxis, hemoptysis, hematuria, or intraocular bleeding); History (within the last 5 years) or presence of gastric ulcers. Previous history of duodenal ulcer is acceptable but must have been successfully surgically or medically treated with no further evidence of disease in the past 6 months (from screening); Prior history of abnormal bleeding tendency (ie, prolonged bleeding on dental extraction, tonsillectomy, or previous surgical procedure); Known prior history or presence of thrombocytopenia (platelet count <100,000/mm3) or thrombocytosis (platelet count >500,000/mm3) or recent history (within 6 months) of hemoglobin <10 mg/dL; International normalized ratio (INR) >1.5 or activated partial thromboplastin time (aPTT) > upper limit of normal (ULN) of laboratory reference range at screening; History of major surgery, severe trauma, fracture, or organ biopsy within 3 months prior to enrollment; Prior/concomitant therapy exclusion criteria: Subjects taking prasugrel, clopidogrel, ticlopidine, cilostazol, dipyridamole, warfarin, heparin, direct thrombin inhibitors, or GPIIb/IIIa inhibitors < or = 10 days prior to randomization or during study participation; Use (or planned use) of fibrinolytic agents within 30 days before screening or during study participation; Subjects receiving treatment with nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors exceeding 3 doses per week; Subjects taking proton pump inhibitors (eg, lansoprazole, esomeprazole, omeprazole, pantoprazole, or rabeprazole) < or = 10 days prior to randomization or during study participation; Use or planned use of any herbal supplements < or = 10 days prior to randomization or during study participation; Use or planned use of the following strong inhibitors of various CYP pathways < or =10 days prior to randomization or during study participation: ciprofloxacin, cimetidine, fluvoxamine, estradiol, ethinylestradiol, fluconazole, amiodarone, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, erythromycin, telithromycin, itraconazole, ketoconazole, fluconazole, nefazodone, or grapefruit-containing products; Use or planned use of the following strong inducers of various CYP pathways < or = 10 days prior to randomization or during study participation: rifampin, barbiturates, carbamazepine, dexamethasone, or St. John's Wort; Female subjects taking hormonal contraception or hormonal replacement therapy during study participation; General exclusion criteria: Investigative site personnel directly affiliated with the study or immediate family of investigative site personnel directly affiliated with the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted; Daiichi Sankyo or Eli Lilly employees; Currently enrolled in, or discontinued within the last 30 days from, any clinical study involving an investigational drug or device; Have previously completed or withdrawn from this study; Women who are known to be pregnant and/or who receive a positive serum pregnancy test result, and/or who have given birth within the past 90 days, and/or who are breastfeeding; Results of clinical laboratory tests at the time of screening that are judged to be clinically significant for the subject, as determined by the Investigator; Known allergies or intolerance to aspirin and/or thienopyridines (prasugrel, clopidogrel, or ticlopidine); Evidence of significant active neuropsychiatric disease, alcohol abuse, or drug abuse, in the Investigator's opinion; Evidence of active hepatic disease or any of the following: positive human immunodeficiency virus antibodies; positive hepatitis C antibody; positive hepatitis B surface antigen; serum alanine transaminase, aspartate transaminase, or gamma-glutamyltransferase > or = 3 × ULN of laboratory reference range; or bilirubin > or = 2 × ULN of laboratory reference range at screening; Subjects who are unwilling to make themselves available for the duration of the study and who will not abide by the research unit policy and procedure and study restrictions.

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br>Prasugrel 10 mg film-coated tablet daily dose × 10 days. To maintain blinding, placebo film-coated tablets matching clopidogrel in appearance will be given daily × 10 days to subjects in the prasugrel treatment group. In addition, aspirin 81 mg to 325 mg daily will be taken. | Drug: Prasugrel<br>* One 10 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.<br>* Other names: Effient;|
| Active Comparator: Clopidogrel<br>Clopidogrel 75 mg film-coated tablet daily dose x 10 days To maintain blinding, placebo film-coated tablets matching prasugrel in appearance will be given daily × 10 days to subjects in the clopidogrel treatment group. In addition, aspirin 81 mg to 325 mg daily will be taken. | Drug: Clopidogrel<br>* One 75 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.<br>* Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. | IPA will be measured by the Accumetrics P2Y12 Assay Device. Response will be assessed in P2Y12 Reaction Units and as Platelet Reactivity Index (vasodilator-stimulated phosphoprotein assay). | Baseline to day 10 for Active Treatment Periods 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status | Day 10 occurs in each treatment period at which time data collections are made. 12.1.4. Responders and Poor Responders Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU >235 and a VASP PRI >50%, as assessed 24 hours after the 9th maintenance dose. | Day 10 for Active Treatment Periods 1 and 2 | 
| Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status | Day 10 occurs in each treatment period at which time data collections are made. Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU >235 and a VASP PRI >50%, as assessed 24 hours after the 9th maintenance dose. | Day 10 for Active Treatment Periods 1 and 2 | 
| Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 |  | Day 10 for Active Treatment Periods 1 and 2 | 
| Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% | Numerous studies have established an association between high on-treatment platelet reactivity with clopidogrel and an increased risk for post-PCI ischemic events. In this study, the percentages of responders and poor responders following treatment with prasugrel and clopidogrel were compared. Poor responders were defined based on an Accumetrics VerifyNow PRU >235 and a VASP PRI >50%, as assessed 24 hours after the 9th maintenance dose. | Day 10 for Active Treatment Periods 1 and 2 | 
| Characterization of the Pharmacokinetics (PK) Area Under Curve (AUC)(0-Last) of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers | Blood samples for determination of plasma concentrations of the prasugrel active metabolite, clopidogrel active metabolite, and clopidogrel inactive metabolite will be collected following the administration of the 10th (last) maintenance dose of each of the 2 Active Treatment Periods at 0.5, 1, 2, 4, and 6 hours post-dose. | After dose on Day 10 of Active Treatment Periods 1 and 2 | 
| Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers |  | After dose on Day 10 of Active Treatment Periods 1 and 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thienopyridine, antiplatelet, prasugrel, clopidogrel