A MULTICENTER, DOSE RANGING SAFETY AND PK STUDY OF ARIMOCLOMOL IN ALS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：本研究的主要目的是评估Arimoclomol的安全性和耐受性，在80名ALS患者中，与安慰剂相比，三种剂量（每天75，150和300 mg）治疗12周。 Arimoclomol是一种小分子，在应激条件下上调细胞中的热休克蛋白。 当在ALS的突变型超氧化物歧化酶转基因小鼠模型中在发病前和发病时给予时，Arimoclomol将存活期延长了5周。 Arimoclomol延迟治疗小鼠中运动神经元的死亡，并延迟运动单位电位的相关损失。 当在ALS的体内模型中进行测试时，Arimoclomol的效果大于大多数其他化合物，包括阿舒唑和米诺环素。 ALS是一种严重且最终致命的疾病，目前还没有已知的有效治疗方法。 任何被证明可以减缓疾病进程的化合物都将在临床上具有直接的重要性;此外，积极的结果将增强我们对ALS潜在生物学的理解。 方法：本研究是一项多中心、双盲、安慰剂对照的ALS门诊患者研究。 将入组10家临床试验机构的80例受试者。 受试者将每天接受安慰剂、25 mg tid、50 mg tid或100 mg tid Arimoclomol。 所有80例受试者将接受治疗，以确定12周每日治疗后的安全性和耐受性。 随访访视将在第2、4、8和12周进行。 还将进行为期4周的治疗后安全性评估。 四周后，一部分受试者将入院接受血清和CSF药代动力学研究。 注：本研究的药代动力学部分将不在本研究中心进行。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objective of this study is to assess the safety and tolerability of Arimoclomol, at three dosages (75, 150 and 300 mg per day) as compared with placebo over 12 weeks of treatment in 80 patients with ALS. RESEARCH PLAN: Arimoclomol is a small molecule that up-regulates heat shock proteins in cells under stress. When given both pre-symptomatically and at disease onset in a mutant superoxide dismutase transgenic mouse model of ALS, Arimoclomol extends survival by five weeks. Arimoclomol delays the death of motor neurons in treated mice and delays the associated loss of motor unit potentials. The effect of Arimoclomol is greater than that found with most other compounds, including Riluzole and Minocycline, when tested in this in vivo model of ALS. ALS is a severe and ultimately fatal disease, for which there is no known effective treatment. Any compound proven to slow the course of the illness will be immediate importance clinically; moreover, a positive outcome will enhance our understanding of the underlying biology of ALS. METHODS: This study is a multicenter, double-blind, placebo-controlled study of outpatients with ALS. Eighty subjects at 10 centers will be enrolled. Subjects will receive placebo, 25 mg tid, 50 mg tid, or 100 mg tid Arimoclomol daily. All 80 subjects will receive treatment to determine safety and tolerability after 12 weeks of daily treatment. Follow-up visits will occur at 2, 4, 8, and 12 weeks. There will also be a 4-week post-treatment safety assessment. After four weeks, a subset of participants will be admitted to the hospital for a serum and CSF pharmacokinetic study. NOTE: The pharmacokinetic part of this study will not be done at this study site.