COMBINATION DRUG SELECTION TRIAL IN AMYOTROPHIC LATERAL SCLEROSIS

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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. This project is part of research into safe and effective neuroprotective therapies for amyotrophic lateral sclerosis (ALS), a progressive and incurable neurodegenerative disorder. Multiple mechanisms involved in neurodegeneration lead to neuronal demise in ALS. This proposal has several unique features. First, it will compare in human ALS the neuroprotective potential of two combinations of agents that influence different mechanisms of neurodegeneration. The combinations of minocycline/creatine and celecoxib/creatine have shown additive effects in the SOD mouse model of ALS, reducing neurodegeneration and prolonging survival more than individual agents alone. Second, it will use an important new phase II selection trial design to determine which combination is superior. Specific Aim 1 is to determine which drug combination best slows deterioration in the ALSFRS-R. The selection trial design allows the simultaneous study of groups of medications with the goal of selecting a superior treatment. The selection is based on pre-defined statistical procedures that have a high probability of correct selection (PCS) when an agent exists that has sufficiently superior true efficacy compared to its competitor. Selection trials require smaller sample sizes than conventional superiority trials, and the group sequential feature will further enhance efficiency in allowing early termination with selection of a promising treatment. Specific Aim 2 is to establish whether the combinations are safe and well tolerated in conjunction with riluzole, the only currently FDA approved medication for ALS. The secondary outcome measures are safety and tolerability, and change in function as detected by the forced vital capacity (FVC, percent predicted), Timed Get Up and Go Test (TGUG), quality of life and survival.