An Assessment of Prasugrel on Healthy Adults and Sickle Cell Adults

Anemia, Sickle Cell Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01178099
• Other study ID #: 13746
• Secondary ID: H7T-MC-TAEJ
• Status: Completed
• Phase: Phase 1
• First received: August 6, 2010
• Last updated: January 12, 2012
• Start date: July 2010
• Est. completion date: January 2011

Study information

• Verified date: January 2012
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: National Health Service
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Anemia, Sickle Cell

Intervention

Drug:
• Prasugrel
Oral, daily for 12 days

Locations

Country	Name	City	State
United Kingdom	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	London	UK

Sponsors (2)

Lead Sponsor	Collaborator
Eli Lilly and Company	Daiichi Sankyo Co., Ltd.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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 of dosing up to 8 hours post-dose on Day 1 and Day 12	No
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.	Day 1, Day 12	No
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.	Baseline, Day 12	No
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.	Day 1, Day 12	No
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).	Baseline, Day 12	No
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%	Day 12	No
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.	Baseline, Day 12	No
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).	Baseline, Day 12	No
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%	Day 12	No
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.	Day 1, Day 12	No
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.	Baseline, Day 12	No
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.	Baseline, Day 12	No
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).	Baseline, Day 12	No
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.	Baseline, Day 12	No
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%	Day 12	No