Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).
BackgroundPlatelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study.MethodsThe primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients.ResultsThere were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.ConclusionsDespite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.
BackgroundPatient diaries and pain scales can capture the course and complications of pain managed at home in children. The Faces Pain Scale-Revised (FPS-R) is a validated scale showing reliability in children, but it has not been validated in children with sickle cell disease (SCD).ObjectiveThe purpose of this study was to evaluate comprehension and usability of an electronic modified version of the FPS-R among pediatric patients with SCD.MethodsThis was a cross-sectional, qualitative study involving in-person interviews with children/adolescents from the USA and their parents/legal guardians. Interviews involved cognitive debriefing and usability testing of the FPS-R.ResultsIn total, 22 children with SCD aged 4–17 years participated. Children aged 4–6 were generally unable to demonstrate clear understanding of the FPS-R and its response scale. Overall, children aged ≥7 years understood the instrument and could complete it on the electronic device, although children aged 7–8 often needed assistance from the parent. Children aged 9–17 years were able to read and complete the instrument independently. Most participants considered the electronic device easy to use.ConclusionsThe FPS-R was shown to be a comprehensible and usable pain measure for children aged 7–17 with SCD and to be beneficial for future clinical studies.
DOVE presents a unique opportunity to determine whether antiplatelet therapy reduces frequency of patient-reported VOC and daily vaso-occlusive pain in a global study of children with SCA.
3213 Introduction: There are few approved treatments for children with sickle cell disease (SCD) who experience painful vaso-occlusive crises (VOC). Evidence suggests a pathophysiologic role for platelets in SCD, in general, and in VOC, specifically. Thrombocytosis is common, and markers of platelet activation, are elevated in both children and adults with SCD. This activation may be mediated by adenosine diphosphate (ADP) released from hemolysis of sickled erythrocytes. Accordingly, platelets are a rational therapeutic target to explore with the aim to reduce the frequency and severity of VOC. Therefore, we studied prasugrel, an irreversible P2Y12 ADP receptor antagonist that inhibits platelet activation and aggregation, in children with SCD. The primary objective was to identify doses of prasugrel that produced a 30–50% inhibition of platelet activation for use in a pediatric phase 3 study of efficacy. Methods: We conducted a phase 2, open-label, multi-center, adaptive-design, dose-ranging, pharmacokinetic (PK) and pharmacodynamic (PD) study of prasugrel in children with SCD. Males and females 2–17 years of age (inclusive) with SCD (HbSS and HbSβ0-thalassemia genotypes) were eligible. Treatment was initiated with single prasugrel doses expected to have no effect and dosage was increased in accordance with an adaptive design for improved safety and dosage identification. Patients were to receive up to 3 single doses of prasugrel with the second and third doses being administered 14±4 days after the previous dose. Doses of prasugrel were increased or decreased based on the PD response to previous doses in the same patient and/or other patients. Demographic characteristics were also considered for dose assignment in order to balance age, body weight, and sex across the dose range that produced a 30–50% inhibition of platelet aggregation. Platelet inhibition was evaluated by the VerifyNow™ (VN) P2Y12 assay and the vasodilator-associated simulated phosphoprotein (VASP) phosphorylation assay. These PD measures were assessed at screening and 4 hours after each single prasugrel dose. Venous blood samples were collected 0.5 h, 1 h, 1.5 h, 2 h, and 4 h post-dose for PK analysis of prasugrel's active metabolite to calculate the area under the concentration-time curve (AUC). The PK/PD analyses were conducted to describe the relationship between prasugrel's active metabolite AUC and platelet inhibition. Spearman correlation statistics were used to assess the relationship between dose and PD parameters. Results: A total of 24 patients, ranging in age from 4 to 17 years of age, received at least one dose of prasugrel. The mean age was 11.0 years; 58.3% were female; 87.5% had HbSS and 12.5% had HbSβ0-thalassemia. Body weight ranged from 14.4 to 80.1 kg. Patients received single doses of prasugrel ranging from 0.03 to 0.60 mg/kg. A single-dose range of 0.30–0.50 mg/kg produced mean 30–50% inhibition in platelet activation by the VN assay whereas a single-dose range of 0.40–0.50 mg/kg produced mean 30–50% inhibition in the VASP assay. Minimal PD response was observed at single doses, up to approximately 0.25 mg/kg. Above 0.25 mg/kg, PD response increased with dose. The single 0.60 mg/kg dose produced >50% inhibition by both VN and VASP assays. In general, higher doses resulted in increased exposure to prasugrel's active metabolite. Increased variability in exposure and in PD response was seen at higher doses. The PD results demonstrate correlation between dose and 4-hour VN P2Y12 percent inhibition. Prasugrel appeared to be safe and well tolerated in this small patient sample. Three serious adverse events occurred in 2 patients; none of which were considered possibly related to prasugrel. No hemorrhagic events were observed, and no subjects discontinued participation due to an adverse event. Conclusions: These single-dose data will contribute to a population modeling strategy that targets the desired steady state range of platelet inhibition (30–50%) for a subsequent phase 3 clinical trial of the efficacy and safety of prasugrel for the reduction of VOC in children with SCD. Daily maintenance doses will be evaluated in a subsequent part of the current study. Disclosures: Styles: Eli Lilly and Company: Consultancy. Off Label Use: Inhibition of platelet activation by prasugrel in pediatric patients with sickle cell disease. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Heiselman:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heeney:Novartis: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Consultancy. Redding-Lallinger:Eli Lilly and Company: Research Funding. Small:Eli Lilly and Company: Employment, Equity Ownership. Moser:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership.
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