A Study of Prasugrel in Pediatric Participants With Sickle Cell Disease (SCD)

Study Overview
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Brief Summary
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The main purpose of the study is to evaluate the efficacy and safety of the study drug known as prasugrel for the reduction of Vaso-Occlusive Crisis events in pediatric participants with sickle cell disease. The study will also investigate reduction in daily pain in children who have sickle cell disease.

Detailed Description
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The submission database was validated for data reported through the data cutoff date for the submission database lock (SDBL). The SDBL data cutoff was 17 July 2015 for all participants except for 2 in the youngest age group, for whom the SDBL data cutoff occurred on 08 August 2015. The data cutoff date for SDBL corresponds to the primary completion date for the study. The SDBL occurred on 31 August 2015. The study was stopped following SDBL and review of the topline information indicated that the primary and secondary efficacy endpoints were not met. Subsequently, the Sponsor requested that participants discontinue study drug immediately and that discontinuation visits for all active study participants be conducted as soon as feasible. After the data cutoff date for SDBL, the Sponsor continued to collect safety data through the final participants contact; some additional efficacy data were collected through the final visit. The last patient visit (LPV) occurred on 17 December 2015, which corresponds to the study completion date and led to the planned supplemental database lock (PSDBL) on 22 January 2016. This supplemental data base was originally designed to capture additional blinded and randomized information to enhance safety data for labeling should the study have been positive. The safety information contained in this record reflects the entire safety information and reflects the information from the supplemental data base lock in January of 2016. The efficacy information contained in this record reflects the information collected through primary completion date in the submission database. Primary analyses of the major efficacy objectives were repeated using the entire double-blind period data from the PSDBL and did not change the original conclusions and were consistent with the results from the original efficacy analyses included in the SDBL.

Official Title
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A Phase 3, Double-Blind, Randomized, Efficacy and Safety Comparison of Prasugrel and Placebo in Pediatric Patients With Sickle Cell Disease.

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have SCD [homozygous sickle cell (HbSS) or hemoglobin (HbS) Beta^0 thalassemia] Are participants with SCD who have had ≥2 episodes of vaso-occlusive crisis (VOC) in the past year Have a body weight ≥19 kilograms (kg) and are ≥2 and <18 years of age, inclusive at the time of screening If participants are ≥2 and ≤16 years of age, must have had a transcranial Doppler within the last year Exclusion Criteria: History of: transient ischemic attack (TIA)/ ischemic or hemorrhagic stroke, severe head trauma, intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm History of abnormal or conditional [velocity in middle or anterior cerebral, or internal carotid artery ≥170 centimeter per second (cm/sec)] transcranial Doppler within the last year History of, or are undergoing treatment with, chronic red blood cell (RBC) transfusion therapy Are at an increased risk for bleeding complications Are receiving chronic treatment with nonsteroidal anti-inflammatory drug (NSAID)s and cannot be switched to another analgesic

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br>Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily. | Drug: Prasugrel<br>* Administered orally<br>* Other names: Efient;|
| Placebo Comparator: Placebo<br>Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group. | Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Vaso-Occlusive Crisis (VOC) Events Per Participant Per Year (Rate of VOC) | The VOC is a composite endpoint of painful crisis or acute chest syndrome. Events that occurred within 7 days from the prior event onset date were not counted as a new episode. Data collected through the primary completion date reported below. | Randomization through 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monthly Rate of Days of Analgesic Use | Monthly rate of days of analgesic use was measured through participant diaries and was calculated for each participant by summing the number of days they reported analgesic use divided by the number of diary entries completed in the month. A month was defined as 4 weeks (28 days). The monthly rate was set to missing if there were more than 14 missing entries for analgesic use in a specific month. Data collected through the primary completion date are presented below. | Randomization through 9 Months | 
| Quarterly Rate of School Absence Due to Sickle Cell Pain | Quarterly rate of school absence due to sickle cell pain was measured through participant diaries and was calculated for each participant by summing the number of days with school absence due to sickle cell pain divided by the number of school dates in the quarter. A quarter was defined as 12 weeks. The quarterly rate was set to missing if there were more than 6 weeks of missing diary entries during a specific quarter. Data collected through the primary completion date are presented below. | Randomization through 9 Months | 
| Time to First Transient Ischemic Attack (TIA)/Ischemic Stroke |  | Randomization through 24 Months | 
| Number of Days Hospitalized for VOC | The total length of hospitalization in days for VOC was calculated for each participant. Data collected through the primary completion date are presented below. | Randomization through 24 Months | 
| Time From Randomization to First and Second VOC | Data collected through the primary completion date are presented below. | Randomization to First VOC and Second VOC respectively (up to 24 Months) | 
| Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention | Medical intervention was defined as any medical evaluation resulting in therapy or further investigation, as determined by a trained medical professional. Data collected from the first dose of study medication through 10 days after last dose of study medication during the double blind study period are presented below. | First Dose through 24 Months | 
| Monthly Rate of Days With Pain | Monthly rate of days with pain was measured through participant diaries using a modified version of the Faces Pain Scale-Revised (FPS-R). Each day participants selected the face on the scale that reflected their worst pain related to sickle cell disease (SCD) on that day. This pain scale contains six faces corresponding to the pain intensity of 0, 2, 4, 6, 8 or 10, in which 0 denotes no pain and 10 denotes the worst pain possible. Any day the participant selected a face other than face 0 was considered a day with pain. Monthly rate of days with pain was calculated for each participant by summing the number of days reported with any pain divided by the number of non-missing diary entries completed in the month. A month was defined as 4 weeks (28 days).The monthly rate was set to missing if there were more than 14 missing entries for the FPS-R in a specific month. Data collected through the primary completion date are present below. | Randomization through 9 Months | 
| Monthly Mean in Faces Pain Scale-Revised Score | Each day participants selected the face on the FPS-R scale that reflected their worst pain related to sickle cell disease (SCD) on that day. Monthly mean in FPS-R score was calculated for each participant by summing the FPS-R score divided by the number of non-missing diary entries completed in the month. This pain scale contains six faces corresponding to the pain intensity of 0, 2, 4, 6, 8 or 10, in which 0 denotes no pain and 10 denotes the worst pain possible. A month was defined as 4 weeks (28 days). The monthly mean in FPS-R score was set to missing if there were more than 14 missing entries for the FPS-R in a specific month. Data collected through the primary completion date are presented below. | Randomization through 9 Months | 
| Number of Painful Crisis Events Per Participant Per Year (Rate of Painful Crisis) | A painful crisis is defined as an onset of moderate to severe pain that lasts at least 2 hours for which there is no explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids, ketorolac, or other analgesics prescribed by a health care provider (HCP) in a medical setting such as a hospital, clinic, emergency room visit, or telephone management. The painful crisis that occurred within 7 days from the prior event onset date was not counted as a new episode. Data collected through the primary completion date are presented below. | Randomization through 24 Months | 
| Number of Hospitalizations for VOC Per Participant Per Year (Rate of Hospitalizations) | Hospitalization that occurred within 7 days of the prior event onset date were not counted as a new episode. Data collected through the primary completion date are presented below. | Randomization through 24 Months | 
| Number of Acute Chest Syndrome Per Participant Per Year (Rate of Acute Chest Syndrome) | Acute chest syndrome was defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. Acute chest syndrome that occurred within 7 days of the prior event onset date was not counted as a new episode. Data collected through the primary completion date are presented below. | Randomization through 24 Months | 
| Number of Red Blood Cell (RBC) Transfusions Due to Sickle Cell Disease (SCD) Per Participant Per Year (Rate of RBC Transfusions) | RBC transfusions that occurred within 7 days of the prior event onset date were not counted as a new episode. Data collected through the primary completion date are presented below. | Randomization through 24 Months |