An Assessment of Prasugrel on Healthy Adults and Sickle Cell Adults

Study Overview
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Brief Summary
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The purpose of this study is to measure the exposure to prasugrel's active metabolite and the pharmacodynamic effects of prasugrel treatment in people with Sickle Cell Disease (SCD).

Official Title
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A Pharmacokinetic and Pharmacodynamic Assessment of Prasugrel in Healthy Adults and Adults With Sickle Cell Disease

Conditions
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Anemia, Sickle Cell

Intervention / Treatment
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* Drug: Prasugrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are 50 to 100 kilograms (kg), inclusive, at the time of screening. Have signed informed consent. If female, agree to use a reliable method of birth control during the study or are women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Control Subjects - Are healthy adults as determined by medical history, physical examination, and other screening procedures. Sickle cell disease (SCD) Subjects - Subjects on hydroxyurea must be on a stable dose for the 30 days prior to enrollment without signs of hematologic toxicity at screening. SCD Subjects - Are adults with SCD (hemoglobin SS [HbSS], Hb S beta0 thalassemia, Hb SC or Hb S beta+ thalassemia genotype) without a diagnosis of acute vaso-occlusive crisis (VOC) requiring medical intervention in an emergency department, infusion center, or as an inpatient) within the month prior to screening. Exclusion Criteria: Have a concomitant medical illness (for example, terminal malignancy) that, in the opinion of the investigator, is associated with reduced survival over the expected treatment period (approximately 1 month). Exhibit severe hepatic dysfunction (cirrhosis, portal hypertension, or alanine aminotransferase [ALT] for aspartate aminotransaminase [AST]≥3 times upper limit of normal [ULN]). Exhibit severe renal dysfunction defined as Cockcroft-Gault creatinine clearance<30 milliliters per minute (ml/min), or requiring chronic dialysis. Creatine clearance = [(140-Age) * Mass (in kg)] \ [72 * Serum creatinine (in milligrams per deciliter [mg/dL])]. Exhibit any contraindication for antiplatelet therapy. Have a history of intolerance or allergy to approved thienopyridines. Exhibit any signs or symptoms of an infection. Have a hematocrit <18%. Exhibit any history of bleeding diathesis, bleeding requiring in-hospital treatment, or papillary necrosis. Have active internal bleeding. Have a history of spontaneous bleeding requiring in-hospital treatment. Have gross hematuria or >300 red blood cells (RBC)/high-powered field (HPF) on urinalysis at the time of screening. History of previous intraocular hemorrhage which required treatment with surgery or laser, or evidence of active intraocular haemorrhage. Have a prior history of transient ischemic attack (TIA), ischemic stroke, hemorrhagic stroke or other intracranial hemorrhage. Have a known history of intracranial neoplasm, arteriovenous malformation, or aneurysm. Have clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding. Have an international normalized ratio (INR) known to be >1.5 (INR testing not required for study entry). Have had recent surgery (within 30 days prior to screening) or are scheduled to undergo surgery within the next 60 days. Have a recent history of clinically significant menorrhagia. Have used any aspirin, warfarin, or thienopyridine in the 10 days prior to enrollment. Have used any non-aspirin non-steroidal anti-inflammatory drug (NSAID) in the 3 days prior to enrollment. Anticipate using aspirin, warfarin, NSAID, thienopyridine or other antiplatelet agent during the study period. Are women who are known to be pregnant, who have given birth within the past 90 days, or who are breastfeeding. Regular use of drugs of abuse and/or unacceptable positive findings on urinary drug screening (a positive urinary drug screening for sleep inducers or pain medications in subjects with SCD will be considered as an acceptable finding). Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br>Participants received a single 10 milligram (mg) dose on Day 1 (single dose [SD]), followed by either 5 mg/day (for participants<60 kilograms [kg]) or 7.5 mg/day (for participants≥60 kg) for an additional 11 days (multiple dose [MD]). | Drug: Prasugrel<br>* Oral, daily for 12 days<br>* Other names: Efient;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve (AUC) From Time of Dosing Through the Sampling Time of the Last Quantifiable Concentration [AUC(0-tlast)] for Prasugrel's Active Metabolite, R-138727 | The AUC of Prasugrel's active metabolite, R-138727, was calculated through the sampling time of the last quantifiable plasma concentration [AUC(0-tlast)]. Geometric Least Squares (LS) Means were obtained. The log-transformed AUC was analyzed with a mixed effect model with dose, population, dose*population interaction as fixed effects, and participant as a random effect. | Time of dosing up to 8 hours post-dose on Day 1 and Day 12 | 
| Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | Cmax was observed from the data and used to calculate Geometric Least Squares (LS) Means. The log-transformed Cmax was analyzed with a mixed effect model with dose, population, dose*population interaction as fixed effects, and participant as a random effect. | Day 1, Day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Maximum Platelet Aggregation (MPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | MPA to 5 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 the platelet-rich plasma stimulated with a platelet activator, such as ADP, relative to platelet-poor plasma (100% light transmittance). The LTA results were collected as MPA, for which low values indicate strong platelet inhibition. | Baseline, Day 12 | 
| Area Under the Plasma Concentration-Time Curve (AUC) From Time of Dosing Through the Sampling Time of the Last Quantifiable Concentration [AUC(0-tlast)] of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | AUC was calculated through the sampling time of the last quantifiable plasma concentration [AUC(0-tlast)]. Geometric Least Squares (LS) Means were obtained. The log-transformed AUC was analyzed with a mixed effect model with dose, population, dose*population interaction as fixed effects, and participant as a random effect. | Day 1, Day 12 | 
| Change From Baseline in the Residual Platelet Aggregation (RPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | RPA is the percentage aggregation as measured by LTA at 6 minutes after the addition of 5 μM ADP. LTA is an assay that measures platelet aggregation by determining the amount of light transmitted through a cuvette containing the platelet-rich plasma stimulated with a platelet activator, such as ADP, relative to platelet-poor plasma (100% light transmittance). | Baseline, Day 12 | 
| Inhibition of Platelet Aggregation (IPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | IPA is calculated as a percent decrease of maximum platelet aggregation (MPA) from baseline using the following formula: ([MPA at baseline - MPA postbaseline] / MPA at baseline) x 100% | Day 12 | 
| Change From Baseline in the Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | MPA to 20 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 the platelet-rich plasma stimulated with a platelet activator, such as ADP, relative to platelet-poor plasma (100% light transmittance). The LTA results were collected as MPA, for which low values indicate strong platelet inhibition. | Baseline, Day 12 | 
| Change From Baseline in the Residual Platelet Aggregation (RPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | RPA is the percentage aggregation as measured by light transmission aggregometry (LTA) at 6 minutes after the addition of 20 μM ADP. LTA is an assay that measures platelet aggregation by determining the amount of light transmitted through a cuvette containing the platelet-rich plasma stimulated with a platelet activator, such as ADP, relative to platelet-poor plasma (100% light transmittance). | Baseline, Day 12 | 
| Inhibition of Platelet Aggregation (IPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | IPA is calculated as a percent decrease of maximum platelet aggregation (MPA) from baseline using the following formula: ([MPA at baseline - MPA postbaseline] / MPA at baseline) x 100% | Day 12 | 
| Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | Cmax was observed from the data and used to calculate geometric Least Squares (LS) Means. The log-transformed Cmax was analyzed with a mixed effect model with dose, population, dose*population interaction as fixed effects, and participant as a random effect. | Day 1, Day 12 | 
| Change From Baseline in the P2Y12 Reaction Units (PRU) Device Reported P2Y12 Percent Inhibition at Day 12 | PRU device reported VerifyNow percent inhibition is reported by Accumetrics VerifyNow™ P2Y12 (VN-P2Y12) assay, a point-of-care device that measures platelet aggregation with single-use, disposable cartridges. | Baseline, Day 12 | 
| Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | PRI was calculated by vasodilator-associated phosphoprotein (VASP) phosphorylation assay using flow cytometry (FC) and a VASP assay using enzyme-linked immunosorbent assay (ELISA). The PRI indicates the level of P2Y12 inhibition. A low PRI reflects strong inhibition of P2Y12, whereas a high PRI reflects weak/absent inhibition of P2Y12. | Baseline, Day 12 | 
| Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AUC to 20 micromolar (μM) adenosine diphosphate (ADP), 6.5μM ADP, Collagen, and thrombin receptor activator for peptide 6 (TRAP-6) were calculated by whole blood multi-electrode aggregometry (MEA) assay. Platelet aggregation was continuously recorded for 5 minutes and quantified as area under the aggregation curve, measured in aggregation units*minutes (AU*min). | Baseline, Day 12 | 
| Change From Baseline in the Percent Aggregation to 20 µM Adenosine Diphosphate (ADP) at Day 12 | Percent aggregation was assessed by Plateletworks® ADP assay, a whole blood-based test of platelet aggregation for the assessment of platelet inhibition. The assay determines the change in single platelet count due to activation and aggregation by ADP and inhibition thereof by antiplatelet agents. | Baseline, Day 12 | 
| P2Y12 Reaction Units (PRU)-Derived VerifyNow (VN) Percent Inhibition at Day 12 | PRU-derived VN percent inhibition is calculated as a percent decrease of PRU from baseline using the following formula: ([PRU at baseline - PRU at time of post baseline] / PRU at baseline) x 100% | Day 12 |