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
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.
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