Study Rationale Sickle cell disease (SCD) is a genetic blood disorder in which vaso-occlusive crisis (VOC) is the principle complication. A VOC can result in recurrent hospitalization and cause a variety of serious organ system complications, disabilities, and even death. There is evidence linking platelets to sickle-cell pathology, specifically VOC. In addition, some studies have suggested a benefit of antiplatelet therapy in reducing biomarkers of platelet activation as well as the frequency and severity of painful crisis with SCD (Osamo et al. 1981; Cabannes et al. 1984). As a result, there is potential that prasugrel, an inhibitor of platelet activation and aggregation, may be beneficial in the prevention of VOC in pediatric patients with SCD. Study H7T-MC-TADO (hereafter referred to as Study TADO) is a Phase 3 study of the efficacy and safety of prasugrel for the reduction of VOC in pediatric patients with SCD.

Objectives:

Double-Blind Treatment Period:

Primary Objective

The primary objective of this study is to assess the efficacy of prasugrel compared to placebo in pediatric patients with sickle-cell disease (SCD) as measured by reduction in the rate of vaso-occlusive crisis (VOC), which is a composite endpoint of painful crisis or acute chest syndrome. 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 in a medical setting such as a hospital, clinic, emergency room visit, or telephone management. Acute chest syndrome is defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray.

Major Secondary Efficacy Objectives

Assess the efficacy of prasugrel compared to placebo in pediatric patients with SCD by assessment of the following endpoints in a fixed-sequence gatekeeping procedure:

1. the reduction in the rate of sickle cell-related pain as recorded in patient pain diaries

2. the reduction in the rate of hospitalization for VOC

3. the reduction in the rate of painful crisis

4. the reduction in the rate of acute chest syndrome

5. the reduction in the rate of red blood cell (RBC) transfusion due to SCD

6. the reduction in the intensity of sickle cell-related pain as recorded in patient pain diaries

7. the reduction in the use of analgesics as recorded in patient pain diaries

8. the reduction in school absence secondary to sickle-cell pain as recorded in patient pain diaries

Other Secondary Efficacy Objectives

Assess the efficacy of prasugrel compared to placebo in pediatric patients with SCD as measured by:

- incidence of transient ischemic attack (TIA)/ischemic stroke

- time from randomization to first and second VOC

- length of hospitalization for VOC

Safety Objectives

Assess the safety of prasugrel compared to placebo in pediatric patients with SCD as measured by:

- the incidence of hemorrhagic events requiring medical intervention, including hemorrhagic stroke

- the incidence of hemorrhagic and nonhemorrhagic treatment-emergent adverse events (TEAEs)

- the tolerability of prasugrel compared to placebo as measured by rate of permanent study drug discontinuation due to hemorrhagic and nonhemorrhagic TEAEs

Pharmacokinetic Objective

Assess the pharmacokinetics (PK) of prasugrel in pediatric patients with SCD by characterizing the exposure to prasugrel’s active metabolite (Pras-AM)

Pharmacodynamic Objectives

Characterize pharmacodynamics (PD) related to the antiplatelet effects of prasugrel compared to placebo in pediatric patients with SCD

Evaluate in a substudy the attenuation of platelet activation by prasugrel compared to placebo in pediatric patients with SCD by measuring whole-blood and urine biomarkers of platelet activation

Pharmacokinetic-Pharmacodynamic Objective

Assess the PK-PD relationship between prasugrel’s active metabolite (Pras-AM) and antiplatelet effects of prasugrel in pediatric patients with SCD

Open-Label Extension:

To evaluate long-term safety of prasugrel in pediatric patients with SCD

To evaluate long-term efficacy of prasugrel in pediatric patients with SCD

Study Design: Phase 3, double-blind, randomized, parallel group, multinational study in outpatient pediatric patients with SCD. During the double-blind treatment period, patients will be titrated to once-daily doses of either placebo or prasugrel for a minimum of 9 months to a maximum of 24 months. There will be an optional openlabel extension with a minimum duration of 12 months in which all patients will be titrated to an appropriate prasugrel dose.

Diagnosis and Main Criteria for Inclusion and Exclusions: Patients include males and females with SCD (homozygous sickle cell [HbSS] and hemoglobin [HbS] β0 thalassemia genotypes) who have had ≥ episodes of VOC in the past year, with a body weight ≥9 kg, and are 2 to <18 years of age. Exclusion criteria include patients who have had a diagnosis of acute VOC within 15 days prior to screening, history of abnormal or conditional transcranial Doppler within the last year, history of, or are undergoing treatment with chronic RBC transfusion; those who have hepatic dysfunction (defined as alanine aminotransferase ≥x upper limit of normal), renal dysfunction (defined as patients requiring chronic dialysis or those with creatinine ≥.2 mg/dL), hematocrit <18%, prior history of hemorrhagic or ischemic stroke, a TIA, or intracranial hemorrhage, patients with bleeding disorders, anticipated use of aspirin, warfarin, other antiplatelet/anticoagulant medications during the study period, or if these medications are used within 10 days prior to dosing; or females known to be pregnant, who have given birth within the past 90 days, or who are breastfeeding.

Investigational Product, Dosage, and Mode of Administration: At Visits 1 to 3 in the double-blind treatment period, VerifyNow®P2Y12 reaction units (PRU) will be measured as required in order to titrate to the appropriate maintenance dose for each patient. Prasugrel will be administered as an orally disintegrating tablet at a maintenance dose that targets a PRU range of 231 to 136 that corresponds to an inhibition of platelet aggregation of approximately 30% to 60%. Dosing is weight based (mg/kg) and administered daily.

Planned Duration of Treatment:

Double-Blind Treatment Period: 9 months minimum treatment, 24 months maximum treatment Open-Label Extension Treatment Period: minimum of 12 months

Reference Therapy, Dose, and Mode of Administration: Study drug administered orally daily

Criteria for Evaluation:

Efficacy:

Rate of sickle cell-related pain as recorded in patient pain diaries

Rate of hospitalization for VOC

Rate of painful crisis

Rate of acute chest syndrome

Rate of RBC transfusion due to SCD

Intensity of sickle cell-related pain as recorded in patient pain diaries

Use of analgesics as recorded in patient pain diaries

School attendance as recorded in patient pain diaries

Incidence of TIA/ ischemic stroke

Time from randomization to first and second VOC

Length of hospitalization for VOC

Safety:

Incidence of hemorrhagic events requiring medical intervention, including hemorrhagic stroke

Incidence of hemorrhagic and nonhemorrhagic TEAEs

Rate of study drug discontinuation due to adverse events (AEs) and hemorrhagic AEs

Pharmacokinetics:

Area under the concentration-time curve for Pras-AM

Pharmacodynamics:

VN and vasodilator-associated stimulated phosphoprotein (VASP) will be used to measure platelet inhibition

Pharmacokinetics-Pharmacodynamics:

PRU and/or VASP platelet reactivity index (PRI) and their relationship to area under the concentrationtime curve for Pras-AM

Statistical Methods:

Efficacy:

Primary efficacy endpoint: The rate of recurrent episodes of VOC will be compared between treatment groups using the Andersen-Gill model with the stratification variables hydroxyurea use and age group included in the model. The within-patient interdependency is accounted for by using the robust standard error estimates for the estimated regression parameters.

Major secondary efficacy endpoints: A fixed-sequence gatekeeping testing strategy for the major secondary efficacy objectives will be implemented to control the overall type I error rate at a 2-sided alpha level of 0.05. The major secondary efficacy endpoints will be tested in the following order: (1) The reduction in the rate of sickle cell-related pain as recorded in patient pain diaries versus placebo using a mixed-effects model repeated measures (MMRM) analysis; (2) The reduction in the hospitalization rate for VOC using the Andersen-Gill model; (3) The reduction in the rate of painful crisis using the Andersen-Gill model; (4) The reduction in the rate of acute chest syndrome using the Andersen-Gill model; (5) The reduction in the rate of RBC transfusion due to SCD using the Andersen-Gill model; (6) The reduction in the intensity of sickle cell-related pain as recorded in patient pain diaries using a MMRM analysis; (7) The reduction in the use of analgesics using a MMRM analysis; and (8) The reduction inschool absence using a MMRM analysis.

Safety: Safety endpoints will be summarized using descriptive statistics, and treatment group comparisons will be performed using a Fisher’s exact test. Descriptive statistics will be used to summarize safety endpoints during the open-label extension.

Pharmacokinetics: The PK of the measured Pras-AM concentrations will be evaluated using a population PK model and/or non-compartmental methods.

Pharmacodynamics: Summary statistics will be provided for each PD parameter. The comparison between treatment groups will be carried out with the analysis of covariance (ANCOVA) model and MMRM analysis.

Pharmacokinetics-Pharmacodynamics: Relationship between exposure to Pras-AM andPRU and/or PRI will be evaluated by descriptive or population-based methods.