本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2310151

摘要内容如下：

背景

C型尼曼-皮克病是一种罕见的溶酶体贮积症。我们评估了N-乙酰-L-亮氨酸（NALL）治疗C型尼曼-皮克病的安全性和有效性，NALL是一种可能改善溶酶体和代谢功能障碍的药物。

方法

在这项双盲、安慰剂对照、交叉试验中，我们将4岁或4岁以上经遗传学证实患有C型尼曼-皮克病的患者按1:1的比例随机分配接受NALL治疗12周，然后接受安慰剂治疗12周，或接受安慰剂治疗12周，然后接受NALL治疗12周。NALL或匹配的安慰剂每天口服2至3次，4至12岁的患者接受基于体重的剂量（每天2至4 G），13岁或以上的患者接受每天4 G的剂量。主要终点是共济失调评估和评级量表的总分（Sara；范围为0至40，得分越低表明神经功能状态越好）。次要终点包括临床总体改善印象、脊髓小脑性共济失调功能指数和改良残疾评定量表的评分。每组两个12周周期的交叉数据包括在NALL与安慰剂的比较中。

结果

共招募了60名5至67岁的患者。主要分析中使用的平均基线Sara总分在接受第一剂NALL（60名患者）之前为15.88，在接受第一剂安慰剂（59名患者）之前为15.68；1名患者从未接受安慰剂治疗）。接受NALL治疗12周后，Sara总分相对于基线的平均（±SD）变化为-1.97±2.43分，接受安慰剂治疗12周后为-0.60±2.39分（最小二乘均数差为-1.28分；95%置信区间，-1.91至-0.65；P<0.001）。次要终点的结果通常支持主要分析的结果，但这些结果未进行多重比较调整。NALL和安慰剂的不良事件发生率相似，未发生与治疗相关的严重不良事件。

结论

在C型尼曼-皮克病患者中，NALL治疗12周的神经功能状态优于安慰剂。需要更长的时间来确定该药物对C型尼曼-皮克病患者的长期影响。（由Intrabio提供资金；ClinicalTrials.gov编号，NCT05163288；Eudract编号:2021-005356-10。）

英文原文如下：

Abstracts

BACKGROUND  Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.

METHODS  In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.

RESULTS  A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.

CONCLUSIONS  Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

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