CLINICAL PILOT TRIAL OF CREATINE IN AMYOTROPHIC LATERAL SCLEROSIS (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. OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the voluntary motor system resulting in generalized muscle weakness, dysphagia, dysarthria, and eventual respiratory failure. It has been hypothesized that in ALS there may be involvement of oxidative free radical damage and impaired mitochondrial energy metabolism that could in turn lead to excitotoxic cell death. Creatine, an agent that improves mitochondrial function, has been shown to be neuroprotective in animal models of ALS and Huntington's disease. The objective of this project is to determine whether creatine slows disease progression in patients with ALS. The specific aims of this proposal are to: (1) Determine whether treatment with creatine results in an acute increase in muscle strength and whether that effect is sustained with chronic therapy; (2) Determine whether chronic treatment with creatine will slow by 35% the progressive deterioration of motor and pulmonary function in patients with ALS; and (3) Determine whether administration of loading doses of creatine followed by chronic treatment is safe in patients with ALS. RESEARCH PLAN AND METHODS: This is a phase 2, double-blind, placebo-controlled, randomized, multi-center safety and efficacy study of creatine in 200 subjects with ALS. Each center will recruit approximately 20 patients. Patients will be randomized to receive treatment with creatine (10 grams/d for 5 days followed by 5 grams/d for duration of study) vs. placebo. The patients will be evaluated weekly for the first 3 weeks, monthly for 3 months, and then bimonthly until the completion of the study. Patients will then be offered participation in an open-label study until the data from the blinded portion of the study can be analyzed. The primary outcome measure is change in disease progression rate as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups (bilateral shoulder and elbow flexion and extension). Secondary endpoints include the rate of decline of forced vital capacity (FVC, percent predicted), manual muscle strength, grip strength, the change in the ALS functional rating scale (ALSFRS-R) and the SF-12 (quality of life instrument), the safety and tolerability of creatine, and survival.