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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2314793

摘要内容如下：

背景

先天性血栓性血小板减少性紫癜（TTP）由ADAMTS13的严重遗传性缺陷引起。重组ADAMTS13和标准疗法（血浆衍生产品）作为常规预防或按需治疗用于先天性TTP患者的疗效和安全性尚不清楚。

方法

在这项3期、开放标签、交叉试验中，我们以1:1的比例将患者随机分配到两个6个月的预防期，即使用重组ADAMTS13（40 IU/kg体重，静脉给药）或标准治疗，然后进行交替治疗。此后，所有患者再接受6个月的重组ADAMTS13治疗。该中期分析的触发因素是至少30名患者完成试验。主要转归是急性TTP事件。评估了TTP的表现、安全性和药代动力学。发生急性TTP事件的患者可以接受按需治疗。

结果

共有48名患者接受了随机分组；32人完成了审判。重组ADAMTS13预防期间未发生急性TTP事件，而1例患者在标准预防治疗期间发生急性TTP事件（平均年度事件率，0.05）。血小板减少症是最常见的TTP表现（年度事件率，重组ADAMTS13为0.74，标准治疗为1.73）。71%接受重组ADAMTS13治疗的患者和84%接受标准治疗的患者发生不良事件。研究者认为与试验药物有关的不良事件发生在9%的重组ADAMTS13患者和48%的标准治疗患者中。在接受重组ADAMTS13治疗的患者和接受标准治疗的8名患者中，均未出现因不良事件而中断或停用试验药物的情况。重组ADAMTS13治疗期间未产生中和抗体。与标准治疗后的19%相比，重组ADAMTS13治疗后的平均最大ADAMTS13活性为101%。

结论

在先天性TTP患者使用重组ADAMTS13进行预防期间，ADAMTS13活性达到正常水平的约100%，不良事件的严重程度通常为轻度或中度，TTP事件和表现罕见。（由Takeda Development Center Americas和Baxalta Innovations资助；ClinicalTrials.gov编号：NCT03393975。）

英文原文如下：

Abstracts

BACKGROUND  Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known.

METHODS  In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment.

RESULTS  A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy.

CONCLUSIONS  During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

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