Anemia, Sickle Cell
Conditions
Brief summary
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).
Interventions
DRUGPrasugrel
Oral, daily for 12 days
Sponsors
Daiichi Sankyo Co., Ltd.
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Time of dosing up to 8 hours post-dose on Day 1 and Day 12 | 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. |
| Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | Day 1, Day 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Residual Platelet Aggregation (RPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline, 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). |
| Inhibition of Platelet Aggregation (IPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | 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% |
| Change From Baseline in the Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline, 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. |
| Change From Baseline in the Residual Platelet Aggregation (RPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline, 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). |
| Inhibition of Platelet Aggregation (IPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | 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% |
| Change From Baseline in the Maximum Platelet Aggregation (MPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline, 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. |
| Change From Baseline in the P2Y12 Reaction Units (PRU) Device Reported P2Y12 Percent Inhibition at Day 12 | Baseline, 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. |
| Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | Baseline, 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. |
| Change From Baseline in the Area Under the Aggregation Curve at Day 12 | Baseline, 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). |
| Change From Baseline in the Percent Aggregation to 20 µM Adenosine Diphosphate (ADP) at Day 12 | Baseline, 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. |
| P2Y12 Reaction Units (PRU)-Derived VerifyNow (VN) Percent Inhibition at Day 12 | 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% |
| Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | Day 1, Day 12 | 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. |
| 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 | Day 1, Day 12 | 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prasugrel 10 mg SD; 5 mg MD (Healthy) Participants received a single 10-milligram (mg) dose on Day 1 (single dose \[SD\]), followed by 5 mg/day (for participants\<60 kilograms \[kg\]) for an additional 11 days (multiple dose \[MD\]). | 4 |
| Prasugrel 10 mg SD; 7.5 mg MD (Healthy) Participants received a single 10-mg dose on Day 1 (SD), followed by 7.5 mg/day (for participants≥60 kg) for an additional 11 days (MD). | 9 |
| Prasugrel 10 mg SD; 5 mg MD (Sickle Cell Disease) Participants received a single 10-mg dose on Day 1 (SD), followed by 5 mg/day (for participants\<60 kilograms \[kg\]) for an additional 11 days (MD). | 4 |
| Prasugrel 10 mg SD; 7.5 mg MD (Sickle Cell Disease) Participants received a single 10-mg dose on Day 1 (SD), followed by 7.5 mg/day (for participants≥60 kg) for an additional 11 days (MD). | 9 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Prasugrel 10 mg SD; 5 mg MD (Healthy) | Total | Prasugrel 10 mg SD; 7.5 mg MD (Sickle Cell Disease) | Prasugrel 10 mg SD; 5 mg MD (Sickle Cell Disease) | Prasugrel 10 mg SD; 7.5 mg MD (Healthy) |
|---|---|---|---|---|---|
| Age Continuous | 24.8 years STANDARD_DEVIATION 3 | 27.9 years STANDARD_DEVIATION 7.6 | 29.6 years STANDARD_DEVIATION 6.8 | 28.0 years STANDARD_DEVIATION 14.8 | 27.6 years STANDARD_DEVIATION 6.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 24 Participants | 9 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 16 Participants | 9 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 9 Participants | 0 Participants | 0 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 4 participants | 26 participants | 9 participants | 4 participants | 9 participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 2 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 15 Participants | 7 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 4 | 5 / 9 | 8 / 13 | 3 / 4 | 7 / 9 | 10 / 13 |
| serious Total, serious adverse events | 0 / 4 | 0 / 9 | 0 / 13 | 0 / 4 | 0 / 9 | 0 / 13 |
Outcome results
Primary
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 frame: Time of dosing up to 8 hours post-dose on Day 1 and Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Prasugrel Healthy Participants | 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 | 10 mg SD (overall) | 68.2 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 7.5 mg MD (N=9, 8) | 50.4 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 5 mg MD (N=4, 4) | 39.8 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 10 mg SD (overall) | 71.5 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 7.5 mg MD (N=9, 8) | 45.2 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 5 mg MD (N=4, 4) | 36.0 nanogram*hour per milliliter (ng*h/mL) |
90% CI: [0.829, 1.33]Mixed Models Analysis
90% CI: [0.718, 1.12]Mixed Models Analysis
90% CI: [0.656, 1.25]Mixed Models Analysis
Primary
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.
Time frame: Day 1, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | 10 mg SD (overall) | 67.9 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | 7.5 mg MD (N=9, 8) | 62.5 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | 5 mg MD (N=4, 4) | 40.9 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | 10 mg SD (overall) | 64.7 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | 7.5 mg MD (N=9, 8) | 38.2 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Active Metabolite, R-138727 | 5 mg MD (N=4, 4) | 42.0 nanogram per milliliter (ng/mL) |
90% CI: [0.664, 1.37]Mixed Models Analysis
90% CI: [0.436, 0.86]Mixed Models Analysis
90% CI: [0.625, 1.68]Mixed Models Analysis
Secondary
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.
Time frame: Day 1, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Prasugrel Healthy Participants | 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 | 7.5 mg MD for R-95913 (N=9, 8) | 49.4 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 5 mg MD for R-106583 (N=4, 4) | 151 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 10 mg SD (overall) for R-106583 | 248 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 10 mg SD (overall) for R-119251 | 32.7 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 5 mg MD for R-95913 (N=4, 4) | 33.6 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 7.5 mg MD for R-119251 (N=9, 8) | 22.2 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 7.5 mg MD for R-106583 (N=9, 8) | 213 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 5 mg MD for R-119251 (N=4, 4) | 20.1 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Healthy Participants | 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 | 10 mg SD (overall) for R-95913 | 52.8 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 5 mg MD for R-119251 (N=4, 4) | 16.3 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 10 mg SD (overall) for R-95913 | 80.2 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 7.5 mg MD for R-95913 (N=9, 8) | 70.9 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 5 mg MD for R-95913 (N=4, 4) | 47.9 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 10 mg SD (overall) for R-106583 | 241 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 7.5 mg MD for R-106583 (N=9, 8) | 174 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 5 mg MD for R-106583 (N=4, 4) | 144 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 10 mg SD (overall) for R-119251 | 38.3 nanogram*hour per milliliter (ng*h/mL) |
| Prasugrel Sickle Cell Disease | 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 | 7.5 mg MD for R-119251 (N=9, 8) | 23.8 nanogram*hour per milliliter (ng*h/mL) |
90% CI: [1.1, 2.1]Mixed Models Analysis
90% CI: [1.06, 1.94]Mixed Models Analysis
90% CI: [0.918, 2.21]Mixed Models Analysis
90% CI: [0.742, 1.27]Mixed Models Analysis
90% CI: [0.633, 1.05]Mixed Models Analysis
90% CI: [0.658, 1.38]Mixed Models Analysis
90% CI: [0.833, 1.65]Mixed Models Analysis
90% CI: [0.779, 1.48]Mixed Models Analysis
95% CI: [0.51, 1.3]Mixed Models Analysis
Secondary
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).
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 6.5 µM ADP at Baseline (Day 1) | 76.5 aggregation units*minutes (AU*min) | Standard Deviation 13.2 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 6.5 µM ADP, Day 12 Change (N=13, 11) | -49.538 aggregation units*minutes (AU*min) | Standard Deviation 17.145 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 20 µM ADP at Baseline (Day 1) | 85.0 aggregation units*minutes (AU*min) | Standard Deviation 19 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 20 µM ADP, Day 12 Change (N=13, 11) | -54.077 aggregation units*minutes (AU*min) | Standard Deviation 22.552 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to Collagen at Baseline (Day 1) | 85.5 aggregation units*minutes (AU*min) | Standard Deviation 12.7 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to Collagen, Day 12 Change (N=13, 11) | -7.692 aggregation units*minutes (AU*min) | Standard Deviation 11.707 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to TRAP-6 at Baseline (Day 1) | 120.2 aggregation units*minutes (AU*min) | Standard Deviation 18.6 |
| Prasugrel Healthy Participants | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to TRAP-6, Day 12 Change (N=13, 11) | -7.846 aggregation units*minutes (AU*min) | Standard Deviation 20.136 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to TRAP-6, Day 12 Change (N=13, 11) | -2.818 aggregation units*minutes (AU*min) | Standard Deviation 33.045 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 6.5 µM ADP at Baseline (Day 1) | 106.4 aggregation units*minutes (AU*min) | Standard Deviation 27.9 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to Collagen at Baseline (Day 1) | 102.3 aggregation units*minutes (AU*min) | Standard Deviation 25.4 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 6.5 µM ADP, Day 12 Change (N=13, 11) | -63.182 aggregation units*minutes (AU*min) | Standard Deviation 24.153 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to TRAP-6 at Baseline (Day 1) | 131.5 aggregation units*minutes (AU*min) | Standard Deviation 30.7 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 20 µM ADP at Baseline (Day 1) | 108.1 aggregation units*minutes (AU*min) | Standard Deviation 27.7 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to Collagen, Day 12 Change (N=13, 11) | -3.000 aggregation units*minutes (AU*min) | Standard Deviation 26.038 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Area Under the Aggregation Curve at Day 12 | AU*min to 20 µM ADP, Day 12 Change (N=13, 11) | -66.182 aggregation units*minutes (AU*min) | Standard Deviation 26.084 |
p-value: 0.396ANCOVA
p-value: 0.288ANCOVA
p-value: 0.095ANCOVA
p-value: 0.086ANCOVA
Secondary
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.
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 85.0 percent aggregation | Standard Deviation 15.9 |
| Prasugrel Healthy Participants | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 9) | -43.3 percent aggregation | Standard Deviation 11.7 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 73.4 percent aggregation | Standard Deviation 12.9 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 9) | -30.9 percent aggregation | Standard Deviation 22.6 |
p-value: 0.219ANCOVA
Secondary
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.
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 80.4 percent aggregation | Standard Deviation 23.2 |
| Prasugrel Healthy Participants | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 7) | -49.9 percent aggregation | Standard Deviation 18.7 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 73.1 percent aggregation | Standard Deviation 14.4 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Maximum Platelet Aggregation (MPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 7) | -33.4 percent aggregation | Standard Deviation 30 |
p-value: 0.07ANCOVA
Secondary
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.
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the P2Y12 Reaction Units (PRU) Device Reported P2Y12 Percent Inhibition at Day 12 | Baseline (Day 1) | 12.0 percent inhibition | Standard Deviation 11 |
| Prasugrel Healthy Participants | Change From Baseline in the P2Y12 Reaction Units (PRU) Device Reported P2Y12 Percent Inhibition at Day 12 | Change from Baseline at Day 12 (N=11, 10) | 60.1 percent inhibition | Standard Deviation 19.6 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the P2Y12 Reaction Units (PRU) Device Reported P2Y12 Percent Inhibition at Day 12 | Baseline (Day 1) | 1.0 percent inhibition | Standard Deviation 2.2 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the P2Y12 Reaction Units (PRU) Device Reported P2Y12 Percent Inhibition at Day 12 | Change from Baseline at Day 12 (N=11, 10) | 47.9 percent inhibition | Standard Deviation 17 |
p-value: 0.06ANCOVA
Secondary
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.
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Percent Aggregation to 20 µM Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 91.3 percent aggregation | Standard Deviation 9.8 |
| Prasugrel Healthy Participants | Change From Baseline in the Percent Aggregation to 20 µM Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 10) | -53.0 percent aggregation | Standard Deviation 16.4 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Percent Aggregation to 20 µM Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 74.0 percent aggregation | Standard Deviation 30 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Percent Aggregation to 20 µM Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 10) | -46.7 percent aggregation | Standard Deviation 44.8 |
p-value: 0.083ANCOVA
Secondary
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.
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | Flow Cytometry at Baseline (Day 1), (N=12, 8) | 78.91 percentage PRI | Standard Deviation 10.03 |
| Prasugrel Healthy Participants | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | Flow Cytometry, Day 12 Change, (N=12, 8) | -49.883 percentage PRI | Standard Deviation 22.004 |
| Prasugrel Healthy Participants | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | ELISA at Baseline (Day 1), (N=11, 13) | 94.70 percentage PRI | Standard Deviation 2.39 |
| Prasugrel Healthy Participants | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | ELISA, Day 12 Change (N=11, 12) | -70.436 percentage PRI | Standard Deviation 17.16 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | ELISA, Day 12 Change (N=11, 12) | -68.117 percentage PRI | Standard Deviation 12.856 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | Flow Cytometry at Baseline (Day 1), (N=12, 8) | 59.36 percentage PRI | Standard Deviation 23.31 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | ELISA at Baseline (Day 1), (N=11, 13) | 92.03 percentage PRI | Standard Deviation 5.65 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Platelet Reactivity Index (PRI) of Prasugrel at Day 12 | Flow Cytometry, Day 12 Change, (N=12, 8) | -46.000 percentage PRI | Standard Deviation 27.395 |
p-value: 0.086ANCOVA
p-value: 0.679ANCOVA
Secondary
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).
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Residual Platelet Aggregation (RPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 84.1 percent aggregation | Standard Deviation 16.7 |
| Prasugrel Healthy Participants | Change From Baseline in the Residual Platelet Aggregation (RPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 8) | -67.0 percent aggregation | Standard Deviation 18.1 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Residual Platelet Aggregation (RPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 72.2 percent aggregation | Standard Deviation 12.4 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Residual Platelet Aggregation (RPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 8) | -45.5 percent aggregation | Standard Deviation 32.7 |
p-value: 0.177ANCOVA
Secondary
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).
Time frame: Baseline, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prasugrel Healthy Participants | Change From Baseline in the Residual Platelet Aggregation (RPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 76.9 percent aggregation | Standard Deviation 29.1 |
| Prasugrel Healthy Participants | Change From Baseline in the Residual Platelet Aggregation (RPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 7) | -70.3 percent aggregation | Standard Deviation 27.4 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Residual Platelet Aggregation (RPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Baseline (Day 1) | 72.2 percent aggregation | Standard Deviation 14.1 |
| Prasugrel Sickle Cell Disease | Change From Baseline in the Residual Platelet Aggregation (RPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | Change from Baseline at Day 12 (N=12, 7) | -47.3 percent aggregation | Standard Deviation 35.6 |
p-value: 0.018ANCOVA
Secondary
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%
Time frame: Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Healthy Participants | Inhibition of Platelet Aggregation (IPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | 52.6 percent inhibition | Standard Deviation 13.5 |
| Prasugrel Sickle Cell Disease | Inhibition of Platelet Aggregation (IPA) to 20 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | 38.5 percent inhibition | Standard Deviation 32.2 |
p-value: 0.168ANCOVA
Secondary
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%
Time frame: Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Healthy Participants | Inhibition of Platelet Aggregation (IPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | 61.2 percent inhibition | Standard Deviation 13.1 |
| Prasugrel Sickle Cell Disease | Inhibition of Platelet Aggregation (IPA) to 5 Micromolar (µM) Adenosine Diphosphate (ADP) at Day 12 | 41.7 percent inhibition | Standard Deviation 47.3 |
p-value: 0.06ANCOVA
Secondary
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.
Time frame: Day 1, Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 7.5 mg MD for R-95913 (N=9, 8) | 33.4 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 5 mg MD for R-106583 (N=4, 4) | 38.7 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 10 mg SD (overall) for R-106583 | 68.5 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 10 mg SD (overall) for R-119251 | 24.9 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 5 mg MD for R-95913 (N=4, 4) | 18.4 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 7.5 mg MD for R-119251 (N=9, 8) | 15.5 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 7.5 mg MD for R-106583 (N=9, 8) | 56.8 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 5 mg MD for R-119251 (N=4, 4) | 20.3 nanogram per milliliter (ng/mL) |
| Prasugrel Healthy Participants | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 10 mg SD (overall) for R-95913 | 30.2 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 5 mg MD for R-119251 (N=4, 4) | 15.5 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 10 mg SD (overall) for R-95913 | 45.4 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 7.5 mg MD for R-95913 (N=9, 8) | 36.3 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 5 mg MD for R-95913 (N=4, 4) | 34.4 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 10 mg SD (overall) for R-106583 | 59.8 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 7.5 mg MD for R-106583 (N=9, 8) | 38.7 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 5 mg MD for R-106583 (N=4, 4) | 34.8 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 10 mg SD (overall) for R-119251 | 26.5 nanogram per milliliter (ng/mL) |
| Prasugrel Sickle Cell Disease | Maximum Concentration (Cmax) of Prasugrel's Inactive Metabolites, R-95913, R-106583, and R-119251 | 7.5 mg MD for R-119251 (N=9, 8) | 15.9 nanogram per milliliter (ng/mL) |
90% CI: [1.01, 2.22]Mixed Models Analysis
90% CI: [0.751, 1.58]Mixed Models Analysis
90% CI: [1.09, 3.2]Mixed Models Analysis
90% CI: [0.66, 1.15]Mixed Models Analysis
90% CI: [0.524, 0.886]Mixed Models Analysis
90% CI: [0.612, 1.32]Mixed Models Analysis
90% CI: [0.773, 1.46]Mixed Models Analysis
90% CI: [0.582, 1.06]Mixed Models Analysis
90% CI: [0.648, 1.55]Mixed Models Analysis
Secondary
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%
Time frame: Day 12
Population: All participants who received at least 1 dose of the study drug and have evaluable data, excluding participants with an adverse event (AE) of vomiting that occurred at or before 4-hours postdose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel Healthy Participants | P2Y12 Reaction Units (PRU)-Derived VerifyNow (VN) Percent Inhibition at Day 12 | 65.8 percent inhibition | Standard Deviation 23.4 |
| Prasugrel Sickle Cell Disease | P2Y12 Reaction Units (PRU)-Derived VerifyNow (VN) Percent Inhibition at Day 12 | 47.8 percent inhibition | Standard Deviation 18.6 |
p-value: 0.124ANCOVA