Comparison of Prasugrel and Clopidogrel in Low Body Weight Versus Higher Body Weight With Coronary Artery Disease

Study Overview
=================
Brief Summary
-----------------
The 5-milligram (mg) dose of prasugrel in low body weight (LBW) patients with coronary artery disease produces a pharmacodynamic response within the same therapeutic range as 10-mg dose in higher body weight (HBW) patients.

Official Title
-----------------
A Pharmacokinetic and Pharmacodynamic Comparison of Prasugrel and Clopidogrel in Low Body Weight Versus Higher Body Weight Aspirin-Treated Subjects With Stable Coronary Artery Disease

Conditions
-----------------
Coronary Artery Disease

Intervention / Treatment
-----------------
* Drug: prasugrel
* Drug: clopidogrel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with a history of stable coronary artery disease who are not currently indicated for treatment with a thienopyridine (that is, prasugrel, clopidogrel, or ticlopidine) Provision of written informed consent For women of child-bearing potential only (that is, women who are not surgically or chemically sterilised and who are between menarche and 1 year post menopause), test negative for pregnancy (based on a urine or serum pregnancy test to be performed before randomisation) and agree to use a reliable method of birth control during the study Exclusion Criteria: Unstable coronary artery disease Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Graft Surgery (CABG) within the previous 90 days History of refractory ventricular arrhythmias within the last 6 months; an implanted defibrillator device; congestive heart failure within 6 months prior to screening; major surgery, or severe trauma, fracture or organ biopsy within 3 months prior to enrollment Any planned surgical procedure or any coronary revascularisation (surgical or percutaneous) planned within 60 days following randomisation Any known contraindication to treatment with an antiplatelet agent Significant hypertension at the time of screening or randomisation Clinically significant out-of-range values for platelet count or haemoglobin at screening, in the investigator's opinion, or results of clinical laboratory tests at the time of screening that are judged to be clinically significant for the study population, as determined by the investigator Prior history or presence of significant bleeding disorders, abnormal bleeding tendency, or personal history of coagulation or bleeding disorders. Prior history or clinical suspicion of cerebral vascular malformations, intracranial neoplasm, Transient Ischemic Attack (TIA) or stroke. Prior history of thrombocytopenia or thrombocytosis Use of antiplatelet agents (besides aspirin) within 10 days prior to screening; the use (or planned use) of heparin, oral anticoagulants, or fibrinolytic agents within 30 days of screening; or subjects receiving daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) or cyclooxygenase-2 (COX-2) inhibitors that cannot be discontinued for the duration of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg prasugrel<br> | Drug: prasugrel<br>* Administered orally, daily for 12 days<br>* Other names: CS747;|
| Active Comparator: 10 mg prasugrel<br> | Drug: prasugrel<br>* Administered orally, daily for 12 days<br>* Other names: CS747;|
| Active Comparator: 75 mg clopidogrel<br> | Drug: clopidogrel<br>* Administered orally, daily for 12 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 (Period 1) | MPA to 20 micromolar (μM) ADP was assessed by light transmission aggregometry (LTA), an assay that measures platelet aggregation by determining the amount of light transmitted through a cuvette containing platelet-rich plasma stimulated with a platelet activator, such as ADP, relative to platelet-poor plasma (100% light transmittance). A lower MPA reflects stronger platelet inhibition, whereas a higher MPA reflects weaker inhibition. | Baseline, Day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Vasodilator-Associated Stimulated Phosphoprotein (VASP) at Day 12 of Therapy | VASP phosphorylation levels, expressed as the platelet reactivity index (PRI), reflect the degree of thienopyridine-mediated P2Y12 receptor inhibition and were used to compare prasugrel versus clopidogrel, in low body weight (LBW) participants compared to higher body weight (HBW) participants. PRI was calculated by VASP. The PRI indicates the level of P2Y12 receptor inhibition. A lower PRI reflects stronger inhibition of P2Y12 receptor thus stronger platelet inhibition, whereas a higher PRI reflects weaker inhibition of P2Y12 receptor and weaker platelet inhibition. | Baseline, Day 12 | 
| Change From Baseline in VerifyNow® P2Y12 Reaction Units (PRU) at Day 12 of Therapy | The Accumetrics VerifyNow® P2Y12 assay measures platelet aggregation in whole blood and is reported in PRU. PRU indicates the extent of P2Y12 receptor-mediated platelet aggregation calculated as a function of rate and extent of platelet aggregation in an adenosine phosphate (ADP)-containing channel of the device. A lower PRU reflects stronger inhibition of platelet aggregation, whereas a higher PRU reflects weaker inhibition of platelet aggregation. | Baseline, Day 12 | 
| Pharmacokinetic (PK) Analysis of the Concentration-Time Curve (AUC) | A pharmacokinetic-pharmacodynamic (PK-PD) analysis comparing MPA (LTA) and AUC was conducted as originally intended, however the graphic output is not possible here. Therefore, the PK portion is presented here as AUC and the PD portion is presented in Secondary Outcome Measure #5. AUC was calculated through the last scheduled sampling time of 4 hours [AUC (0-4)] or through the sampling time of the last quantifiable concentration prior to 4 hours. AUC values were denoted AUC(0-tlast) in both instances. | baseline (pre-dose) up to 4 hours post-dose | 
| Change From Baseline in Maximum Platelet Aggregation (MPA) as Measured by Light Transmission Aggregometry (LTA) at Day 12 of Therapy | MPA to 20 micromolar (μM) adenosine diphosphate (ADP) was assessed by LTA, an assay that measures platelet aggregation by determining the amount of light transmitted through a cuvette containing platelet-rich plasma stimulated with a platelet activator, such as ADP, relative to platelet-poor plasma (100% light transmittance). A lower MPA reflects stronger platelet inhibition, whereas a higher MPA reflects weaker inhibition. | Baseline , Day 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Platelet function