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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：本研究的主要目的是在80例ALS患者的12周治疗中，评估三种剂量（75,150和300mg /天）阿利莫洛尔与安慰剂的安全性和耐受性。研究计划：阿利莫洛尔是一种小分子，可在应激状态下上调细胞中的热休克蛋白。在突变型超氧化物歧化酶转基因ALS小鼠模型中，在症状前和发病时给予阿利莫洛尔可延长5周的生存期。阿利莫洛尔延缓治疗小鼠运动神经元的死亡，并延缓相关的运动单位电位损失。在ALS的体内模型中进行测试时，阿利莫洛尔的效果比大多数其他化合物（包括利鲁唑和米诺环素）都要大。ALS是一种严重且最终致命的疾病，目前尚无有效的治疗方法。任何经证实能减缓病程的化合物在临床上都具有直接意义；此外，一个积极的结果将增强我们对ALS潜在生物学的理解。方法：本研究是一项针对门诊ALS患者的多中心、双盲、安慰剂对照研究。10个中心的80名受试者将被纳入研究。受试者将接受安慰剂，每日25mg tid、50mg tid或100mg tid阿利莫洛尔。所有80名受试者将在12周的每日治疗后接受治疗以确定安全性和耐受性。随访将在第2、4、8和12周进行。治疗后还将进行为期4周的安全性评估。四周后，一部分参与者将入院进行血清和脑脊液药代动力学研究。注意：本研究的药代动力学部分将不在本研究地点进行。将通过生命体征和体重、临床实验室测定、心电图、体格检查、不良事件报告以及按照指定治疗剂量完成研究的受试者比例（耐受性）来评估阿利莫洛尔的安全性。特别令人感兴趣的是，在一种可能必须终身服用的药物中，无法忍受的不良经历。鉴于这种疾病的严重程度相当严重的副作用是可以容忍的。副作用概况将用于确定疗效研究中使用的药物剂量。阿利莫洛尔在ALS患者群体中的血液和CSF药代动力学特性将在一部分参与者中确定。由于获得CSF水平需要一个有副作用风险的过程，因此该研究将仅在一个时间点（开始给药后4周）获得CSF水平。注意：本研究的药代动力学部分将不在本研究地点进行。临床相关性：如果阿利莫洛尔在ALS患者中显示出初步的耐受性、安全性和中枢神经系统穿透性，那么该研究的数据将用于支持ALS的疗效研究。

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. The safety of Arimoclomol will be evaluated using vital signs and weight, clinical laboratory determinations, EKG, physical examination, reporting of adverse events, and the proportion of subjects completing the study on assigned treatment dosages (tolerability). Of particular interest would be adverse experiences that would not be tolerable in a drug that might have to be administered life long. Given the severity of the disease fairly severe side effects might be tolerated. The side effect profile will be used to determine the dose of the drug used in the efficacy study. The blood and CSF pharmacokinetic properties of Arimoclomol in the ALS patient population will be determined in a subset of participants. Since obtaining CSF levels require a procedure with a side effect risk, the study will only obtain CSF levels at one time point (4 weeks after initiating dosing). NOTE: the pharmacokinetic part of this study will not be done at this study site. CLINICAL RELEVANCE: Should Arimoclomol show preliminary tolerability, safety and CNS penetration in patients with ALS, the data from the study would then be used to support an efficacy study in ALS.