CLINICAL TRIAL OF CEFTRIAXONE IN SUBJECTS WITH ALS

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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. The study objective is to determine the safety and efficacy of ceftriaxone, a Food and Drug Administration (FDA) approved semi-synthetic third-generation cephalosporin, in subjects with amyotrophic lateral sclerosis (ALS). The study hypothesis is that intravenous (IV) ceftriaxone will prolong survival free of tracheostomy or permanent assisted ventilation (PAV) in patients with ALS. In a National Institute of Neurological Disorders and Stroke (NINDS)-led cooperative group in-vitro screening program of 1040 FDA approved drugs in 29 assays relevant to various neurodegenerative disorders, several cephalosporins, including ceftriazone, showed hits in ALS relevant assays. Efficacy was noted in models screening for compounds that increased expression of the astrocytic glutamate transporter, EAAT2 [1], and in models of superoxide dismutase mediated toxicity. Since completion of the original NINDS screen, it has been shown that ceftriaxone increases EAAT2 promotor activation and subsequent EAAT2 activity in rodent brains. Ceftriaxone also protects motor neurons in culture from excitotoxic cell death [2], and has antioxidant and anti-apoptotic activity [3,4]. We propose a novel study design strategy of nonstop drug development with multiple intermediate analyses to rapidly apply information on cerebrospinal fluid (CSF) penetration and safety of ceftriazone to the development of a phse III efficacy study [5]. An important first step in the proposed study is to determine the CSF pharmacokinetics of ceftriaxone in subjects with ALS (STAGE 1), followed by a safety and tolerability study for a minimum of 16 weeks (STAGE 2), and then a full efficacy trial (STAGE 3)