Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3)

Study Overview
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Brief Summary
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This trial is designed as a phase 2 randomized, double-blind double dummy, active comparator controlled, two-period two-arm crossover study to enroll 40 patients across multiple centers. The study will compare platelet function following a prasugrel loading dose and 1 week of prasugrel maintenance therapy with high-dose clopidogrel loading dose and 1 week of high-dose clopidogrel maintenance therapy in patients with drug treated type 2 diabetes mellitus who have coronary artery disease. Various assays of platelet function will be used in this study. Platelet function will be studied using the following assays: Accumetrics VerifyNowTM P2Y12, Light Transmittance Aggregometry (LTA), Vasodilator-associated stimulated phosphoprotein (VASP), and Thromboelastography (TEG)-platelet mapping.

Official Title
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A Pharmacodynamic Comparison of Prasugrel (LY640315) Versus High Dose Clopidogrel in Subjects With Type 2 Diabetes Mellitus and Coronary Artery Disease.

Conditions
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Diabetes Mellitus, 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: Type 2 Diabetes Mellitus and on oral or parenteral hypoglycemic therapy for at least 1 month. History of Coronary Artery Disease with or without other types of vascular disease (such as peripheral vascular disease). Taking Aspirin 75-325 mg/day for at least 1 week prior to randomization. Between the ages of 18-74 years old. If a woman of child bearing age, must not be pregnant and must agree to use reliable method of birth control during the duration of the study. Exclusion Criteria: Thienopyridine therapy within 30 days or have a defined need for thienopyridine treatment. Coronary Artery Bypass Graft (CABG) or Percutaneous Coronary Intervention (PCI) with no stent placed within 30 days. Planned coronary revascularization Hemoglobin A1c (HbA1c) > or equal to 10 mg/dL within the last 3 months. Received fibrolytic therapy <24 hours prior to randomization. Received non-fibrin-specific fibrinolytic therapy <48 hours prior to randomization. At risk of bleeding. History of ischemic stroke, transient ischemic attack (TIA), intercranial neoplasm, arteriovenous malformation, or aneurysm. Body weight <60 kilograms (kg). International Normalized Ratio (INR) >1.5, platelet count <100,000/mm3, or anemia (hemoglobin <10 gm/dL) within 1 week of study entry. Are receiving or will receive oral anticoagulation or antiplatelet treatment therapy. Are being treated with daily non-steroidal anti-inflammatory drugs (NSAIDS). Are pregnant, breast-feeding or plan to become pregnant.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br>Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose. | Drug: prasugrel<br>* Oral prasugrel 60-mg loading dose, followed by 6-9 days of oral prasugrel 10-mg/day tablet maintenance dose.<br>* Other names: Efient;|
| Active Comparator: Clopidogrel<br>Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose. | Drug: Clopidogrel<br>* Oral clopidogrel 600-mg loading dose, followed by 6-9 days of oral clopidogrel 150-mg/day tablet maintenance dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibition of Platelet Aggregation (IPA) 4 Hours After Loading Dose Assessed by Accumetrics VerifyNow™ P2Y12 Assay | The inhibition of platelet aggregation 4 hours after the loading dose was administered was assessed using the Accumetrics VerifyNow™ P2Y12 assay. Percentage inhibition, as reported by VerifyNow™ P2Y12, was calculated from P2Y12 Reaction Unit (PRU) (rate and extent of adenosine diphosphate [ADP]-stimulated platelet aggregation) and BASE (estimate of baseline platelet reactivity independent of P2Y12 receptor inhibition [reference values]: rate and extent of Thrombin Receptor-Activated Peptide-stimulated platelet aggregation) values as follows: Percentage (%) inhibition = (1-PRU/BASE) x 100. | 4 hours after loading dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibition of Platelet Aggregation at 1- and 24-Hours After Loading Dose (LD) and 24-Hours After Last Maintenance Dose (LMD) Assessed by Accumetrics VerifyNow™ P2Y12 Assay | Inhibition of platelet aggregation 1- and 24-hours after loading dose and 24-hours after last maintenance dose was administered was assessed using Accumetrics VerifyNow™ P2Y12 assay. Percentage inhibition, as reported by VerifyNow™ P2Y12, was calculated from PRU (rate and extent of ADP-stimulated platelet aggregation) and BASE (estimate of baseline platelet reactivity independent of P2Y12 receptor inhibition [reference values]: rate and extent of Thrombin Receptor-Activated Peptide-stimulated platelet aggregation) values as follows: Percentage (%) inhibition = (1-PRU/BASE) x 100. | 1 hour and 24 hours after the loading dose (LD) and 24 hours after the last maintenance dose (LMD) | 
| Maximum Platelet Aggregation (MPA) as Assessed by Light Transmittance Aggregometry (LTA) | Mean platelet aggregation (MPA) to 5 and 20 µM adenosine diphosphate (ADP) was assessed by light transmittance aggregometry (LTA). Platelet aggregation was monitored for a total of 7 minutes after addition of ADP. Maximum platelet aggregation was the maximal aggregation value achieved during the 7-minute observation period following addition of agonists. | Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose | 
| Platelet Reactivity Index (PRI) | Data from the Vasodilator-associated stimulated phosphoprotein assay were reported as the platelet reactivity index (PRI) which was calculated from corrected mean fluorescence intensity (cMFI) following incubation of platelets with either prostaglandin E1 (PGE1) alone or PGE1 plus ADP: Platelet Reactivity Index (%) = [1-(cMFI PGEI+ADP/cMFI PGEI)] x 100. Lower PRI values indicate greater platelet P2Y12 inhibition. | Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose | 
| Inhibition of Platelet Function as Measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate | Thromboelastography (TEG) platelet mapping (MP) maximum amplitude (MA) - Adenosine Diphosphate (ADP) millimeters (mm) at each time point. The TEG-MP MA measures strength of clot formation in whole blood. MA-ADP is the maximal amplitude resulting from fibrin and platelets not blocked by ADP-receptor inhibiting drugs. Fibrin strands in blood sample link a rotating sample cup with a stationary pin suspended by a torsion wire. The degree of platelet contribution to the MA through platelet-fibrin bonding directly influences the magnitude of pin movement and ultimately the amplitude of the tracing. | Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose |