An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A
An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A
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DOI：
10.1186/s13023-014-0199-0
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发表时间：
2014-12-18
影响因子：
3.7
通讯作者：
Cohen, Daniel
中科院分区：
文献类型：
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作者：
Attarian, Shahram;Vallat, Jean-Michel;Cohen, Daniel
背景资料：Charcot-Marie-Tooth 1A型疾病（CMT 1A）是一种罕见的孤儿遗传性神经病，由编码结构性髓鞘蛋白PMP 22的基因的常染色体显性重复引起，可诱导雪旺细胞异常分化和髓鞘形成障碍，最终导致轴突痛苦，然后是损失和肌肉萎缩。我们赞成这样的想法，即当靶向多种疾病相关途径时，疾病可以得到更有效的治疗。因此，在CMT 1A患者中，我们测试了PXT 3003的潜力，PXT 3003是三种已经批准的化合物（巴氯芬，纳洛酮和山梨醇）的低剂量组合。我们的研究在概念上建立在临床前实验的基础上，强调了包括PMP 22下调在内的多效性作用机制。主要目的是评估PXT 3003的安全性和耐受性。次要目的旨在探索性分析PXT 3003在CMT 1A中的功效，以用于设计下一个临床开发阶段（2b/3期）。方法：80名患有轻度至中度CMT 1A的成年患者在四个相等的组中接受双盲1年安慰剂或三个递增剂量的PXT 3003测试之一。通过相关不良事件的发生率评估安全性和耐受性。疗效进行了评估，使用的Charcot-Marie-Tooth神经病变评分（CMTNS）和整体神经病变限制量表（ONLS）作为主要终点，以及各种临床和电生理outcomes.Results：本试验证实了安全性和耐受性的PXT 3003。最高剂量组（HD）显示稳定后改善的一致证据。与所有其他组的汇总相比，HD组中CMTNS和ONLS分别显著改善8%（0.4% - 16.2%）和12.1%（2% - 23.2%），似乎是对治疗最敏感的临床终点，尽管在安慰剂组中它们在1年内具有准稳定性。没有恶化超过一年的患者显着更频繁的HD group.Conclusions：这些结果证实，PXT 3003值得在成人中进一步调查，可以大大有利于CMT 1A诊断的儿童，通常受影响小于成人。
Background: Charcot-Marie-Tooth type 1A disease (CMT1A)is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3).Methods: 80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.Results: This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group.Conclusions: These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.