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

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ClinicalTrials.gov Identifier: NCT01260584
Recruitment Status : Completed
First Posted : December 15, 2010
Results First Posted : December 12, 2012
Last Update Posted : January 9, 2019
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Tracking Information
First Submitted Date  ICMJE December 13, 2010
First Posted Date  ICMJE December 15, 2010
Results First Submitted Date  ICMJE September 19, 2012
Results First Posted Date  ICMJE December 12, 2012
Last Update Posted Date January 9, 2019
Study Start Date  ICMJE November 2010
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 12, 2012)
Inhibition of Platelet Aggregation (IPA) in Prasugrel-treated and Clopidogrel-treated Smokers and Non-smokers Following 9 Days of Maintenance Therapy. [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: December 14, 2010)
  • Inhibition of Platelet Aggregation (IPA) in clopidogrel-treated smokers versus clopidogrel treated non-smokers following 9 days of maintenance therapy with clopidogrel [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    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).
  • Inhibition of Platelet Aggregation (IPA) in prasugrel-treated smokers vs clopidogrel-treated smokers following 9 days of maintenance therapy with prasugrel or clopidogrel. [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    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).
Change History Complete list of historical versions of study NCT01260584 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2012)
  • Assessment of P2Y12 Reaction Units (PRU) by Treatment and Smoking Status [ Time Frame: Day 10 for Active Treatment Periods 1 and 2 ]
    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.
  • Assessment of Vasodilator Stimulated Phosphoprotein (VASP) by Treatment and Smoking Status [ Time Frame: Day 10 for Active Treatment Periods 1 and 2 ]
    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.
  • Responder Rate by Treatment and Smoking Status Based on P2Y12 Reaction Units (PRU) <= 235 [ Time Frame: Day 10 for Active Treatment Periods 1 and 2 ]
  • Responder Rate by Treatment and Smoking Status Based on Platelet Reactivity Index (PRI) <= 50% [ Time Frame: Day 10 for Active Treatment Periods 1 and 2 ]
    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.
  • 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 [ Time Frame: After dose on Day 10 of Active Treatment Periods 1 and 2 ]
    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.
  • Characterization of the Pharmacokinetics (PK) Cmax of the Active Metabolite of Prasugrel and the Active Metabolite of Clopidogrel in Smokers and Non-smokers [ Time Frame: After dose on Day 10 of Active Treatment Periods 1 and 2 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2010)
  • Inhibition of Platelet Aggregation (IPA) in prasugrel-treated smokers versus prasugrel-treated non-smokers following 9 days of maintenance therapy with prasugrel [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    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).
  • Inhibition of Platelet Aggregation (IPA) in prasugrel-treated non-smokers versus clopidogrel-treated non-smokers [ Time Frame: Baseline to day 10 forActive Treatment Periods 1 and 2 ]
    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).
  • Inhibition of Platelet Aggregation (IPA) in prasugrel-treated non-smokers versus clopidogrel-treated smokers [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    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).
  • Inhibition of platelet aggregation (IPA) in prasugrel-treated subjects versus clopidogrel-treated smokers and non-smokers [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    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). This analysis is optional depending on statistical necessity.
  • Percentages of "responders" and "poor responders" for prasugrel and clopidogrel [ Time Frame: Baseline to end of Active Treatment Period 2 ]
  • Characterization of the pharmacokinetics (PK) of the active metabolite of prasugrel and the active and inactive metabolites of clopidogrel in smokers and non-smokers [ Time Frame: After dose on Day 10 of Active Treatment Periods 1 and 2 to 0.5, 1, 2, 4, 6 hours after dose ]
  • Assessment of the impact of smoking status on cytochrome P450 (CYP) 1A2 activity [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
  • Evaluation of the effect of CYP1A2 activity on the active metabolite of prasugrel and the active and inactive metabolites of clopidogrel [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
  • Evaluation of the effect of CYP1A2 activity on the Inhibition of Platelet Aggregation (IPA)and Vasodilator stimulated phosphoprotein (VASP) assay [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    IPA will be measured by the Accumetrics P2Y12 Assay Device
  • Assessment of the impact of known genetic variants in CYP2C19 on the Inhibition of Platelet Aggregation (IPA)and Vasodilator stimulated phosphoprotein (VASP)assay [ Time Frame: Baseline to day 10 for Active Treatment Periods 1 and 2 ]
    IPA will be measured by the Accumetrics P2Y12 Assay Device
  • Assessment of the impact of known genetic variants in CYP2C19 on the active metabolite of prasugrel and the active and inactive metabolites of clopidogrel [ Time Frame: Day 10 to end of Active Treatment Period 2 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease
Official Title  ICMJE The Influence of Smoking Status on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Aspirin-treated Subjects With Stable Coronary Artery Disease
Brief 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.

Detailed Description 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Coronary Artery Disease
Intervention  ICMJE
  • Drug: Prasugrel
    One 10 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.
    Other Name: Effient
  • Drug: Clopidogrel
    One 75 mg film-coated, oral tablet daily x 10 days. In addition, aspirin 81 mg to 325 mg daily will be taken.
    Other Name: Plavix
Study Arms  ICMJE
  • Experimental: Prasugrel
    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.
    Intervention: Drug: Prasugrel
  • Active Comparator: Clopidogrel
    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.
    Intervention: Drug: Clopidogrel
Publications * Gurbel PA, Bliden KP, Logan DK, Kereiakes DJ, Lasseter KC, White A, Angiolillo DJ, Nolin TD, Maa JF, Bailey WL, Jakubowski JA, Ojeh CK, Jeong YH, Tantry US, Baker BA. The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study. J Am Coll Cardiol. 2013 Aug 6;62(6):505-12. doi: 10.1016/j.jacc.2013.03.037. Epub 2013 Apr 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 9, 2011)
110
Original Estimated Enrollment  ICMJE
 (submitted: December 14, 2010)
108
Actual Study Completion Date  ICMJE September 2011
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 74 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01260584
Other Study ID Numbers  ICMJE CS747S-B-U4002
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/
Responsible Party Daiichi Sankyo, Inc.
Study Sponsor  ICMJE Daiichi Sankyo, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul Gurbel, MD Sinai Center for Thrombosis Research
PRS Account Daiichi Sankyo, Inc.
Verification Date November 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP