Ps1584 a Phase Ii Dose‐finding Study of Dalteparin in Children With Vte With or Without Cancer

Abstract

Background: Venous thromboembolism (VTE) is an important clinical concern in children with or without cancer. Experience with dalteparin, a low molecular weight heparin, in the treatment of VTE in adults with cancer has been extensively published, but data in children are limited. Aims: We sought to determine the twice-daily dalteparin dose required to achieve target Anti-Xa levels of 0.5-1.0 IU/mL, as well as its pharmacodynamics (PD), effi cacy, and safety in the treatment of VTE in children <19 years old, with or without cancer. Methods: This prospective, multi-center, Phase 2, open-label study consisted of 3 phases: 1) Dose Adjustment Phase of up to 7 days, in which Anti-Xa levels were measured following the fi rst, second or third dose of dalteparin, until achievement of the target level; 2) PD Phase of up to 7 days, to obtain 2 randomized PD plasma samples for Anti-Xa determination; and 3) Follow-Up Phase, to complete up to 90 days of anticoagulant therapy. Patients were assessed for symptomatic new or progressive (i.e., recurrent) VTE as well as clinically relevant bleeding during treatment. Surveillance VTE imaging was performed at 90 ± 14 days. Results: The safety population consisted of 38 patients who received at least 1 dose of dalteparin (<2 years: n = 3; ≥2 to <8 years: n = 8; ≥8 to <12 years, n = 7; ≥12 to <19 years: n = 20). Twenty-six patients (68%) had a diagnosis of cancer at baseline, of which 23 (88%) were haematological malignancies. The median [range] dalteparin dose required to achieve target Anti-Xa levels decreased with age (<2 years: 207.5 IU/kg [201.5-213.5 IU/kg]; ≥2 to <8 years: 128.15 IU/ kg [123.9-180.3 IU/kg]; ≥8 to <12 years: 125 IU/kg [124.5-152.6 IU/kg]; ≥12 to <19 years: 116.7 IU/kg [99.1-159 IU/kg]) (Figure).Therapeutic Anti-Xa levels were achieved in 90% of patients within a mean (SD) of 2.6 days (1.54 days); the mean (SD) number of dose adjustments per patient was 0.7 (0.98). One patient (3%) developed symptomatic recurrent VTE. No patients reported clinically-relevant bleeding. Four patients (11%) had treatment-related serious adverse events. 62% of patients had complete resolution of their VTE at the end of the 90-day reporting period. Summary/Conclusion:Twice-daily dalteparin dosing achieved therapeutic levels in 90% of children with or without cancer, with a satisfactory tolerability profi le. The median therapeutic doses of dalteparin were higher for the two youngest age cohort groups (<2 years and 2 to <8 years). NCT00952380 Sources of Research Support: This study was sponsored by Pfi zer Ltd.

International pediatric thrombosis network to advance pediatric thrombosis research: Communication from the ISTH SSC subcommittee on pediatric and neonatal thrombosis and hemostasis

“…Not only randomized controlled sponsored registrational trial and one investigator-initiated trial. 21,22 Performing RCTs on anticoagulants in children has proven to be very challenging. The low incidence of pediatric TE has been an important hurdle.…”

“…The only US Food and Drug Administration (FDA)‐approved anticoagulant for use in children >1 month of age is the LMWH dalteparin. FDA approval was based on evidence from two single‐arm multi‐center clinical trials conducted in a total of 52 pediatric patients—including one industry‐sponsored registrational trial and one investigator‐initiated trial 21,22 …”

“…FDA approval was based on evidence from two single-arm multi-center clinical trials conducted in a total of 52 pediatric patients-including one industrysponsored registrational trial and one investigator-initiated trial. 21,22 Performing RCTs on anticoagulants in children has proven to be very challenging. The low incidence of pediatric TE has been an important hurdle.…”