Division of Haematology/Oncology, Department of Paediatrics and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Center for Bleeding and Clotting Disorders, Children's Hospital of Minnesota, Minneapolis, Minnesota, United States.
Thromb Haemost. 2020 May;120(5):737-746. doi: 10.1055/s-0040-1709521. Epub 2020 May 5.
Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis ( = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).
在患有乙型血友病（HB）的儿童中，延长半衰期因子 IX（FIX）预防治疗的长期安全性和疗效数据很少。 paradigm 5 是一项多中心、开放性、单臂、III 期临床试验，评估了每周一次（40IU/kg）预防性非活化凝血因子 IX 聚乙二醇（N9-GP）在先前接受治疗的患者（PTP）中的应用，这些患者年龄均≤12 岁，且 HB（FIX 活性≤2%）。主要终点：抗 FIX 抑制性抗体（≥0.6 个 Bethesda 单位）的发生率。我们报告了一项 5 年分析（n=25，包括具有≥5 年随访的剩余患者），并与 1 年分析（≥52 周暴露）进行了比较。主要阶段共纳入 25 名儿童；22 名进入扩展阶段；17 名在数据截止时仍在试验中。每名患者的中位治疗期：5.6 年/患者；每名患者的 N9-GP 暴露天数中位数：290.0 天。无患者发生抗 FIX 抑制性抗体。未报告其他安全性问题，包括血栓栓塞事件。神经检查未发现任何新的异常发现。16 名（64.0%）患者仍无自发性出血；所有出血均为轻度/中度严重程度；93.0%用 1 至 2 次 N9-GP 注射即可控制。未报告颅内出血。5 年时年化出血率（ABR）非常低（中位数/泊松估计的总体 ABR：0.66/0.99），较 1 年分析时（1.00/1.44）有所降低。1 年和 5 年分析时的中位数/泊松估计的自发性 ABR 中位数分别为：0.00/0.45 和 0.00/0.33。5 年时的平均 FIX 谷值活性：17.9%。PEG 血浆浓度的平均值在 6 个月时达到稳定状态，随着 FIX 谷值活性的增加，略微增加。在 HB（FIX 活性≤2%）的 PTP 中，接受 N9-GP 治疗≥5 年显示出良好的长期安全性和疗效。
