The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Intervention: Prasugrel; Clopidogrel
Intervention description: One 10 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.; One 75 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.
Intervention MeSH terms: Clopidogrel; Prasugrel Hydrochloride
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 110.0
Sex: All
Minimum age: 18 Years
Maximum age: 74 Years
Healthy volunteers: No
Keywords: thienopyridine; antiplatelet; prasugrel; clopidogrel

Summary:

      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.
    

Eligibility criteria:

        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.