Sickle Cell Disease
Conditions
Keywords
Sickle cell disease, pediatrics, SCD, children, child, kids, pain crisis, sickle cell anemia, sickle cell pain
Brief summary
The purpose of this study is to determine the correct prasugrel dosage to be given to children with sickle cell disease (SCD).
Interventions
DRUGPrasugrel
Administered orally
Sponsors
Daiichi Sankyo
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Parts A and B: 0.5, 1, 1.5, 2, 4 hours postdose | 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. |
| Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 4 hours postdose and Part B: at steady state (14 ± 4 days after the start of each new dosage) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Inactive Metabolite | Part A: 0.5, 1, 1.5, 2, 4 hours postdose | 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. |
| Number of Participants With Pain | Part B: Baseline and Day14 ± 4 days postdose in each dosing period | The number of participants who answered yes to the first question in the Sickle Cell Disease Pain (SCD) Questionnaire is reported. Question 1: In the past 2 weeks, did you experience any sickle cell pain? |
| Number of Participants With Hemorrhagic Events Requiring Medical Intervention | Part B: Baseline up to Day 36 | Hemorrhagic events were determined by the study investigator. Medical intervention was defined as any medical attention resulting in therapy or further investigation, as determined by a trained medical professional. |
Countries
United States
Participant flow
Pre-assignment details
The study was conducted in 2 parts: Part A (single-dose range finding phase) then Part B (once-daily repeated dosing phase). Participants completing Part A could, but were not required to, participate in Part B. There were 2 dosing periods during Part B of the study.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Sponsor decision | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Customized ≥12 and ≤17 years | 12 participants |
| Age, Customized ≥2 and ≤5 years | 7 participants |
| Age, Customized ≥6 and ≤11 years | 14 participants |
| Body Mass Index | 18.64 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 4.091 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Genotype HbS Beta^0 Thalassemia | 3 participants |
| Genotype HbSS | 30 participants |
| Height | 139.21 centimeters (cm) STANDARD_DEVIATION 22.663 |
| Race/Ethnicity, Customized Black or African American | 32 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 14 Participants |
| Weight | 38.55 kilograms (kg) STANDARD_DEVIATION 18.785 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 15 | 4 / 9 | 6 / 9 | 6 / 9 |
| serious Total, serious adverse events | 2 / 15 | 2 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
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.
Time frame: Part A: 4 hours postdose and Part B: at steady state (14 ± 4 days after the start of each new dosage)
Population: Participants who received at least 1 dose of prasugrel.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.03 mg/kg (n=2) | 2.0 percentage of platelet inhibition | Standard Deviation 2.83 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.05 mg/kg (n=2) | 0.0 percentage of platelet inhibition | Standard Deviation 0 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.07 mg/kg (n=2) | 0.0 percentage of platelet inhibition | Standard Deviation 0 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.08 mg/kg (n=18) | 7.7 percentage of platelet inhibition | Standard Deviation 9.35 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.09 mg/kg (n=2) | 2.5 percentage of platelet inhibition | Standard Deviation 3.54 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.11 mg/kg (n=1) | 0.0 percentage of platelet inhibition | — |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.13 mg/kg (n=2) | 9.5 percentage of platelet inhibition | Standard Deviation 13.44 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.15 mg/kg (n=2) | 4.0 percentage of platelet inhibition | Standard Deviation 0 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.2 mg/kg (n=2) | 0.0 percentage of platelet inhibition | Standard Deviation 0 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.25 mg/kg (n=3) | 18.0 percentage of platelet inhibition | Standard Deviation 18.52 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.3 mg/kg (n=6) | 42.3 percentage of platelet inhibition | Standard Deviation 27.21 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.35 mg/kg (n=11) | 38.0 percentage of platelet inhibition | Standard Deviation 28.46 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.4 mg/kg (n=14) | 39.1 percentage of platelet inhibition | Standard Deviation 26.77 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.45 mg/kg (n=8) | 35.3 percentage of platelet inhibition | Standard Deviation 27.16 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.5 mg/kg (n=7) | 55.9 percentage of platelet inhibition | Standard Deviation 27.85 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.55 mg/kg (n=1) | 31.0 percentage of platelet inhibition | — |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part A: 0.6 mg/kg (n=3) | 70.3 percentage of platelet inhibition | Standard Deviation 19.22 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part B: 0.06 mg/kg (n=8) | 38.6 percentage of platelet inhibition | Standard Deviation 21.07 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part B: 0.08 mg/kg (n=18) | 37.8 percentage of platelet inhibition | Standard Deviation 25.86 |
| Entire Study Population | Percentage of Platelet Inhibition as Measured by VerifyNow™P2Y12 (VN) | Part B: 0.12 mg/kg (n=8) | 48.1 percentage of platelet inhibition | Standard Deviation 11.29 |
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.
Time frame: Parts A and B: 0.5, 1, 1.5, 2, 4 hours postdose
Population: Participants who received at least 1 dose of prasugrel.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.09 mg/kg (n=2) | 31.3 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 25 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.25 mg/kg (n=3) | 60.7 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 88 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.03 mg/kg (n=2) | 8.68 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 36 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.05 mg/kg (n=2) | 14.5 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 44 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.07 mg/kg (n=2) | 20.8 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 31 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.11 mg/kg (n=1) | 22.2 nanograms*hour per milliliter (ng*hr/mL) | — |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.13 mg/kg (n=2) | 50.3 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 20 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.15 mg/kg (n=2) | 35.2 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 86 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.2 mg/kg (n=2) | 43.7 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 48 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.3 mg/kg (n=6) | 87.9 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 52 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.35 mg/kg (n=11) | 111 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 59 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.4 mg/kg (n=14) | 108 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 55 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.45 mg/kg (n=8) | 136 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 53 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.5 mg/kg (n=7) | 186 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 36 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.55 mg/kg (n=1) | 87.0 nanograms*hour per milliliter (ng*hr/mL) | — |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part A: 0.6 mg/kg (n=3) | 299 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 4 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part B: 0.06 mg/kg (n=7) | 16.3 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 50 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part B: 0.08 mg/kg (n=17) | 27.1 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 20 |
| Entire Study Population | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Prasugrel Active Metabolite (Pras-AM) | Part B: 0.12 mg/kg (n=8) | 38.5 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 15 |
Secondary
Number of Participants With Hemorrhagic Events Requiring Medical Intervention
Hemorrhagic events were determined by the study investigator. Medical intervention was defined as any medical attention resulting in therapy or further investigation, as determined by a trained medical professional.
Time frame: Part B: Baseline up to Day 36
Population: Participants who received at least 1 dose of prasugrel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entire Study Population | Number of Participants With Hemorrhagic Events Requiring Medical Intervention | 0 participants |
Secondary
Number of Participants With Pain
The number of participants who answered yes to the first question in the Sickle Cell Disease Pain (SCD) Questionnaire is reported. Question 1: In the past 2 weeks, did you experience any sickle cell pain?
Time frame: Part B: Baseline and Day14 ± 4 days postdose in each dosing period
Population: Participants who responded to Question 1 of the SCD Questionnaire. A participant could be counted more than once because there were 2 dosing periods during Part B of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entire Study Population | Number of Participants With Pain | 6 participants |
| Part B: Prasugrel Once-Daily Dose (0.06 mg/kg) | Number of Participants With Pain | 4 participants |
| Part B: Prasugrel Once-Daily Dose (0.08 mg/kg) | Number of Participants With Pain | 1 participants |
| Part B: Prasugrel Once-Daily Dose (0.12 mg/kg) | Number of Participants With Pain | 2 participants |
Secondary
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.
Time frame: Part A: 0.5, 1, 1.5, 2, 4 hours postdose
Population: No participants were analyzed.