A Study of Prasugrel in Pediatric Participants With Sickl... | NCT01476696

NCT01476696

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
H7T-MC-TACX	Other Identifier	Eli Lilly and Company

Status Module

Name	Class
Daiichi Sankyo	INDUSTRY

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Part A: Prasugrel Single Dose	Experimental	Prasugrel 0.03 milligrams per kilogram (mg/kg) to 0.60 mg/kg dosage to be titrated up or down based on desired platelet inhibition, administered orally [oral-disintegrating tablet (ODT)], single dose given up to 3 occasions, at different strengths, with up to 18 days between doses.	Drug: Prasugrel
Part B: Prasugrel Once-Daily Dose	Experimental	Daily prasugrel dose (mg/kg) that is expected to achieve mean platelet activation inhibition of 30% administered orally, once daily for 10-18 days and then followed by prasugrel dose (mg/kg) that is expected to achieve mean platelet activation inhibition of 50% administered orally, once daily for 10-18 days, for a total of 20-36 days.	Drug: Prasugrel

Name	Type	Description	Arm Group Labels	Other Names
Prasugrel	Drug	Administered orally	Part A: Prasugrel Single Dose Part B: Prasugrel Once-Daily Dose

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM)	AUC of Pras-AM from time 0 up to the last sampling time of 4 hours postdose [AUC(0-tlast)] is reported by dose administered [0.03, 0.05, 0.07, 0.09, 0.11, 0.13, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, and 0.6 milligrams per kilogram (mg/kg)] during Part A (single-dose range finding phase) and is reported for doses administered on site (0.06, 0.08, and 0.12 mg/kg) during Part B (once-daily repeated dosing phase) of the study. Four participants received the same dose at multiple visits where pharmacokinetic samples were collected.	Parts A and B: 0.5, 1, 1.5, 2, 4 hours postdose
Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN)	Accumetrics VN assay: A point-of-care device that measures platelet aggregation. Percentage of platelet inhibition is reported by dose administered [0.03, 0.05, 0.07, 0.09, 0.11, 0.13, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, and 0.6 milligrams per kilogram (mg/kg)] during Part A (single-dose range finding phase) and also during the once-daily repeated dosing phase in Part B, at steady state, 14 ± 4 days after each new dose (0.06, 0.08, and 0.12 mg/kg) is administered. One participant received the same dose at multiple visits (Part A) and one participant received the same daily dose during both dosing periods in Part B.	Part A: 4 hours postdose and Part B: at steady state (14 ± 4 days after the start of each new dosage)

Secondary Outcomes

Measure	Description	Time Frame
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Inactive Metabolite	AUC of prasugrel inactive metabolite(s) from time 0 up to the last sampling time of 4 hours postdose [AUC(0-tlast)]. Improvements in bioanalytical methodology enabled direct measurement of Pras-AM from plasma, obviating the need to estimate its concentration from inactive downstream metabolite(s). Thus, the AUC of prasugrel inactive metabolite(s) was not analyzed.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Are male or female with SCD [(homozygous sickle cell (HbSS) and hemoglobin S beta ^0 thalassemia (HbS β^0 thalassemia)]
Have a body weight ≥12 kilograms (kg) and are ≥2 to <18 years of age at the time of screening
If participants are ≥2 and ≤16 years of age, have had a transcranial Doppler within the last year
Participants on hydroxyurea must be on a stable dose for the 60 days prior to enrollment without signs of hematologic toxicity at screening
Have a legal representative that is in competent mental condition to provide written informed consent on behalf of the study participant before entering the study. The child may be required to give documented assent, if required by local regulations.
If sexually active, has a negative pregnancy test at screening (if female) and agrees to use a reliable method of birth control during the study (for both males and females)

Exclusion Criteria:

Known to have hemoglobin C sickle cell (HbSC) or hemoglobin S beta ^plus thalassemia (HbS β^+ thalassemia) genotypes
Vaso-occlusive crisis (VOC) requiring medical attention within 15 days prior to screening
Have a concomitant medical illness (for example, terminal malignancy) that in the opinion of the investigator is associated with reduced survival
Hepatic dysfunction characterized by alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN)
Renal dysfunction requiring chronic dialysis or creatinine ≥ 1.5 milligrams per deciliter (mg/dL)
Contraindication for antiplatelet therapy
History of intolerance or allergy to approved thienopyridines (clopidogrel, ticlopidine, or prasugrel)
Participants with a hematocrit <18%
History of abnormal or conditional transcranial Doppler [velocity in middle cerebral or carotid artery ≥170 centimeters per second (cm/sec)] within the last year
Any history of bleeding diathesis
Any history of renal papillary necrosis
Active internal bleeding
History of spontaneous gastrointestinal bleeding
Gross hematuria or > 300 red blood cells (RBC)/high-powered field (HPF) on urinalysis at the time of screening
Any history of vitreous hemorrhage
Prior history of hemorrhagic or ischemic stroke, a transient ischemic attack (TIA), or other intracranial hemorrhage
Have clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding
Platelet count <100,000 per microliter (μl) of blood
Have had recent surgery (within 30 days prior to screening) or are scheduled to undergo surgery within the next 60 days
History of dysfunctional uteral bleeding, in the judgment of the investigator
Treatment with packed RBC or whole blood transfusion therapy within 30 days prior to dosing
Any nonsteroidal anti-inflammatory drug (NSAID) use within 5 days prior to screening
Any aspirin, warfarin, thienopyridine, or other antiplatelet medication use within 10 days prior to dosing
Anticipated use of aspirin, warfarin, thienopyridine, or other antiplatelet medication during the study period

Name	Affiliation	Role
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern Time (UTC-GMT-5 hours, EST)	Eli Lilly and Company	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
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.		Oakland	California	94609

Arm/Group Information

ID	Title	Description
FG000	Part A: Prasugrel Single Dose	Participants who only enrolled in Part A of the study. Part A: 0.03 milligrams per kilogram (mg/kg) up to 0.60 mg/kg Prasugrel, each dose titrated up or down for each participant in order to achieve desired platelet inhibition (20% to 50%). Single dose administered orally [oral-disintegrating tablet (ODT)] up to 3 times, at different mg/kg doses, with up to 18 days between doses.
FG001	Part B: Prasugrel Once-Daily Dose	Participants who only enrolled in Part B of the study. Part B: Daily Prasugrel dose (mg/kg) expected to achieve mean platelet activation inhibition of 30%, administered orally, ODT, once daily for 14 ± 4 days (first dosing period during Part B). Initial dose, 0.08 mg/kg Prasugrel, administered then pharmacodynamic (PD) response measured 4 hours later. Based on 4-hour PD response, each participant assigned to either 0.08 or 0.06 mg/kg Prasugrel, administered orally, once daily for the remainder of the first dosing period in Part B. For the second continuous 14 ± 4-day period, participants were administered 1 of 3 possible doses: 0.06, 0.08, or 0.12 mg/kg depending on their steady-state PD response at the end of the first dosing period, such that the second dose would be unlikely to exceed 50% platelet inhibition. Participants received study drug for a total of 28 ± 8 days during Part B of the study.
FG002	Part A Then Part B: Prasugrel Single Dose Then Once-Daily Dose	Participants who enrolled in Part A and B of study. Part A: 0.03 up to 0.60 mg/kg Prasugrel, each dose titrated up or down for each participant to achieve desired platelet inhibition (20% to 50%). Single dose administered orally, ODT, up to 3 times, at different mg/kg doses, with up to 18 days between doses. Part B: Daily Prasugrel dose (mg/kg) expected to achieve mean platelet activation inhibition of 30%, administered orally, ODT, once daily for 14 ± 4 days (first dosing period in Part B). Initial dose, 0.08 mg/kg Prasugrel, administered then PD response measured 4 hours later. Based on 4-hour PD response, each participant assigned to 0.08 or 0.06 mg/kg Prasugrel once daily for remainder of first dosing period. For second 14 ± 4-day period, participants assigned to 1 of 3 possible doses: 0.06, 0.08, or 0.12 mg/kg depending on steady-state PD response at end of first dosing period, such that the second dose would be unlikely to exceed 50% platelet inhibition.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Entire Study Population	Participants enrolled in Part A, Part A and B, or only Part B of study. Part A: 0.03 up to 0.60 mg/kg Prasugrel, each dose titrated up or down for each participant to achieve desired platelet inhibition (20% to 50%). Single dose administered orally, ODT, up to 3 times, at different mg/kg doses, with up to 18 days between doses. Part B: Daily Prasugrel dose (mg/kg) expected to achieve mean platelet activation inhibition of 30%, administered orally, ODT, once daily for 14 ± 4 days (first dosing period in Part B). Initial dose, 0.08 mg/kg Prasugrel, administered then PD response measured 4 hours later. Based on 4-hour PD response, each participant assigned to 0.08 or 0.06 mg/kg Prasugrel once daily for remainder of first dosing period. For second 14 ± 4-day period, participants assigned to 1 of 3 possible doses: 0.06, 0.08, or 0.12 mg/kg depending on steady-state PD response at end of first dosing period, so that the second dose would be unlikely to exceed 50% platelet inhibition.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Customized			Number

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM)

AUC of Pras-AM from time 0 up to the last sampling time of 4 hours postdose [AUC(0-tlast)] is reported by dose administered [0.03, 0.05, 0.07, 0.09, 0.11, 0.13, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, and 0.6 milligrams per kilogram (mg/kg)] during Part A (single-dose range finding phase) and is reported for doses administered on site (0.06, 0.08, and 0.12 mg/kg) during Part B (once-daily repeated dosing phase) of the study. Four participants received the same dose at multiple visits where pharmacokinetic samples were collected.

Participants who received at least 1 dose of prasugrel.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanograms*hour per milliliter (ng*hr/mL)

Parts A and B: 0.5, 1, 1.5, 2, 4 hours postdose

ID	Title	Description
OG000	Entire Study Population

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part A: Prasugrel Single Dose	Participants who only enrolled in Part A of the study. Part A: 0.03 milligrams per kilogram (mg/kg) up to 0.60 mg/kg Prasugrel, each dose titrated up or down for each participant in order to achieve desired platelet inhibition (20% to 50%). Single dose administered orally [oral-disintegrating tablet (ODT)] up to 3 times, at different mg/kg doses, with up to 18 days between doses.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Hypersplenism	Blood and lymphatic system disorders	MedDRA 15.1	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Sickle cell anaemia	Congenital, familial and genetic disorders	MedDRA 15.1	Systematic Assessment

Title	Organization	Phone	Extension	Email
Chief Medical Officer	Eli Lilly and Company	800-545-5979

ID	Term
D000755	Anemia, Sickle Cell

ID	Term
D000745	Anemia, Hemolytic, Congenital
D000743	Anemia, Hemolytic
D000740	Anemia
D006402	Hematologic Diseases

ID	Term
D000068799	Prasugrel Hydrochloride

ID	Term
D013876	Thiophenes
D013457	Sulfur Compounds
D009930	Organic Chemicals
D010879	Piperazines

Participants enrolled in Part A, Part A and B, or only Part B of study. Part A: 0.03 up to 0.60 mg/kg Prasugrel, each dose titrated up or down for each participant to achieve desired platelet inhibition (20% to 50%). Single dose administered orally, ODT, up to 3 times, at different mg/kg doses, with up to 18 days between doses.

Part B: Daily Prasugrel dose (mg/kg) expected to achieve mean platelet activation inhibition of 30%, administered orally, ODT, once daily for 14 ± 4 days (first dosing period in Part B). Initial dose, 0.08 mg/kg Prasugrel, administered then PD response measured 4 hours later. Based on 4-hour PD response, each participant assigned to 0.08 or 0.06 mg/kg Prasugrel once daily for remainder of first dosing period. For second 14 ± 4-day period, participants assigned to 1 of 3 possible doses: 0.06, 0.08, or 0.12 mg/kg depending on steady-state PD response at end of first dosing period, so that the second dose would be unlikely to exceed 50% platelet inhibition.