Prasugrel/Clopidogrel Maintenance Dose Washout Study

Study Overview
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Brief Summary
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The primary objective of the study is to describe the cumulative proportion of participants who return to baseline platelet P2Y12 receptor function over time (up to 12 days post last maintenance dose) following discontinuation of prasugrel 10 mg daily x 7 days assessed by Accumetrics VerifyNow P2Y12 reaction units (PRU) and described by Kaplan Meier curves. The primary analysis is descriptive and is intended to provide information relating to the return of baseline platelet function following discontinuation of maintenance therapy with either prasugrel or clopidogrel.

Official Title
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Recovery of Platelet Function Following Discontinuation of Prasugrel or Clopidogrel Maintenance Dosing in Aspirin-Treated Subjects With Stable Coronary 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 >/= 18 years and <75 years of age Weight >/= 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 Coronary Artery disease, defined as any of the following: chronic stable angina Prior history of acute coronary syndrome (>/= 30 days before screening) including unstable angina or acute myocardial infarction (ST elevation Myocardial Infarction [STEMI] or non-ST elevation Myocardial Infarction [NSTEMI]), not currently prescribed or currently on thienopyridine therapy; Previous coronary revascularization including percutaneous transluminal coronary angioplasty (PTCA), stent, or coronary artery bypass grafting (CABG) coronary artery disease (>/= 50% obstruction) in at least one coronary vessel after angiography Female subjects who meet one of the following: Women of childbearing potential with a negative serum pregnancy test at screening who are not breast feeding, 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 oral, path, injectable or implantable hormonal contraception, intrauterine device, diaphragm plus spermicide, or female condom plus spermicide. Abstinence, partner's use of condoms, and partner's vasectomy 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. Subjects with a competent mental condition to provide written informed consent before entering the study. Exclusion Criteria: 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 [NYHA] 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 (TIA), 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 of thrombocytopenia (platelet count < 100,000/mm³) or thrombocytosis (platelet count > 500,000/mm³) or recent history (within six months) of hemoglobin < 10 mg/dL Clinically significant out of range values for prothrombin time, activated partial thromboplastin time (aPTT), platelet count, or hemoglobin at screening, in the investigator's opinion 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 glycoprotein IIB/IIIa inhibitors =10 days prior to screening or during study participation The use (or planned use) of fibrinolytic agents within 30 days before screening or during study participation Subjects receiving treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors exceeding 3 doses per week Subjects receiving proton pump inhibitors (PPIs), eg, (lansoprazole, esomeprazole, omeprazole, pantoprazole, or rabeprazole) =10 days prior to screening or during study participation General Exclusion Criteria: Investigator site personnel directly affiliated with the study or immediate family of investigator 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 prior to baseline from, a clinical study involving an off-label use of an investigational drug or device, or concurrently enrolled in a non-observational clinical study or any other type of medical research judged not to be scientifically or medically compatible with this study 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, 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 (HIV) antibodies, positive hepatitis C antibody, positive hepatitis B surface antigen; serum alanine transaminase (ALT), aspartate transaminase (AST), or gamma-glutamyltransferase (GGT) >/= 3 times the upper limit of normal (ULN) laboratory reference range; or bilirubin >/= 2 times the ULN of laboratory reference range at screening Subjects who are unreliable and 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 Subjects who have had an angiogram </= 7 days before randomization

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br>Prasugrel 10mg administered for 7 days followed by a Washout Period up to 12 days. | Drug: Prasugrel<br>* Prasugrel 10mg tablet administered once daily for 7 days. After a 1-day to 14-day screening period, participants will receive active treatment with either prasugrel or clopidogrel for 7 days. If a participant has not missed more than 1 dose of study medication and is unable to attend Visit 3 (Washout Day 1) the day after the 7th day of study medication, the participant may take up to an additional 3 days of study medication and proceed to Visit 3 the day after the last dose. Active treatment will be followed by a 1-day to 12-day Washout Period depending on the time to reach both of the exit criteria.<br>* Other names: Effient;|
| Active Comparator: Clopidogrel<br>Clopidogrel 75mg administered for 7 days followed by a 12 day Washout Period up to 12 days. | Drug: Clopidogrel<br>* Clopidogrel 75 mg tablet administered once daily for 7 days. After a 1-day to 14-day screening period, participants will receive active treatment with either prasugrel or clopidogrel for 7 days. If a participant has not missed more than 1 dose of study medication and is unable to attend Visit 3 (Washout Day 1) the day after the 7th day of study medication, the participant may take up to an additional 3 days of study medication and proceed to Visit 3 the day after the last dose. Active treatment will be followed by a 1-day to 12-day Washout Period depending on the time to reach both of the exit criteria.<br>* Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to Return to Baseline Platelet Function as Assessed by P2Y12 Reaction Units (PRU) Using the Accumetrics VerifyNOW P2Y12 Device Based on the Primary Definition of Return to Baseline | On the first day of the Washout Period (Visit 3), the blood draw for platelet function testing was obtained 24 hours (+/- 6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participant met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/(Baseline PRU) less than or equal to 20%. The results are expressed as cumulative percentage of participants. | up to 12 days after last dose | 
| The Time to Return to Baseline Platelet Function as Assessed by P2Y12 Reaction Units (PRU) Using the Accumetrics VerifyNOW P2Y12 Device Based on the Secondary Definition of Return to Baseline | On the first day of the Washout Period (visit 3), the blood draw for platelet function testing was obtained 24 hours (+/- 6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participant met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/(Baseline PRU) less than or equal to 20%. | up to 12 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day at Which 50%, 75%, and 90% of Participants Returned to Baseline Platelet Function Based on Primary Definition of Return to Baseline Using the Primary Population | On the first day of the Washout Period (Visit 3), the blood draw for platelet function testing was obtained 24 hours (+/-6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participants met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/Baseline PRU less than or equal to 20%. | up to 12 days after last dose | 
| Day at Which 50%, 75%, and 90% of Participants Returned to Baseline Platelet Function Based on Secondary Definition of Return to Baseline Using the Primary Population | On the first day of the Washout Period (Visit 3), the blood draw for platelet function testing was obtained 24 hours (+/-6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participant met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/Baseline PRU less than or equal to 20%. | up to 12 days after last dose | 
| Day at Which 50%, 75%, and 90% of Participants Returned to Baseline Platelet Function Based on the Primary Definition of Return to Baseline Using the Responder Population | On the first day of the Washout Period (Visit 3), the blood draw for platelet function testing was obtained 24 hours (+/-6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participant met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/Baseline PRU less than or equal to 20%. | up to 12 days after last dose | 
| Day at Which 50%, 75%, and 90% of Participants Returned to Baseline Platelet Function Based on the Secondary Definition of Return to Baseline Using the Responder Population | On the first day of the Washout Period (Visit 3), the blood draw for platelet function testing was obtained 24 hour (+/- 6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participant met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/(Baseline PRU) less than or equal to (<=) 20%. | up to 12 days after the last dose | 
| Percentage of Inhibition of Platelet Aggregation on Washout Day 1 | Inhibition of platelet aggregation was assessed by Accumetrics VerifyNow® P2Y12 reaction units (PRU). On the first day of the Washout Period (Visit 3), the blood draw for platelet function testing was obtained 24 hour (+/- 6 hours) after the last dose of study medication. Following Visit 3, platelet function testing was performed during each visit of the Washout Period until the participant met the following exit criteria: (Baseline PRU-PRU) less than or equal to 60 units and (Baseline PRU-PRU)/(Baseline PRU) less than or equal to 20%. | Washout Day 1 | 
| Time to Return to Baseline PRU for the Primary Population Using the Primary Definition of Return to Baseline in Relation to the Inhibition of Platelet Aggregation 24 Hours Following the Last Maintenance Dose | Time to return to baseline PRU (<= 60 units of baseline) dependent upon baseline PRU and platelet % inhibition on Washout Period Day 1 but independent of treatment. The following regression model was derived for predicting number of days to return to baseline PRU where PI(1) represents platelet percentage inhibition on Washout Day 1. Number days to return to baseline PRU derived from: Number days to return to baseline PRU=-3.350+0.079*PI(1)+0.014*baseline PRU. The predicted number of days to return to baseline based on device-derived platelet percentage inhibition is reported for each treatment group. | up to 12 days after the last dose | 

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